Band 33, Heft 8

The leptin melanocortin signaling pathway is playing a pivotal role for body weight regulation. Genetic defects within this cascade are leading to severe hyperphagia and early onset obesity. In most cases, due to persistent hyperphagia the affected patients are not able to stabilize body weight for a longer period of time with conservative treatment strategies based on lifestyle interventions. Therefore, it is of importance to implement alternative treatment options for these patients. This review provides an overview about the published pharmacological treatment attempts in respect to monogenic forms of obesity and summarizes recent research progress about the role of MC4R signaling and POMC derivatives for body weight regulation.

Objectives Evaluate the influence of the genetic variant rs9939609 of the FTO gene on anthropometric characteristics and whether parental obesity is related to children and adolescents being overweight. Methods A total of 2,364 children and adolescents between 6 and 17 years old were genotyped and the lipid profile, plasma glucose level, and anthropometric characteristics were measured to assess adiposity. Results The AA genotype (risk) was associated with higher body mass index (BMI Z-score; p = 0.006), waist circumference (WC; p = 0.001), and triglycerides (p = 0.033). The association of the participants’ adiposity characteristics with the parents’ BMI and FTO genotypes showed an association of the BMI Z-score when either the mother or father was overweight or obese (p = 0.028 and p = 0.029). In the overweight or obese father/eutrophic mother, we also observe an association of FTO rs9939609 with WC (p = 0.039). The effect of these variables on the risk of obesity was also tested: overweight or obese mother (OR = 1.82, p = 0.041), overweight and obese parents (OR = 3.09, p < 0.0001), and FTO rs9939609 AA genotype (OR = 2.08, p = 0.0004) were associated. With regard to altered WC and high body fat percentage (BF%), either overweight or obese parents (OR = 2.39, p < 0.0001; OR = 1.92, p < 0.002) showed an association. The FTO rs9939609 AA genotype (OR = 1.99, p = 0.0002) was associated with altered WC. Conclusions The results show that parental weight also contributes to obesity and may interact with the FTO genetic make-up.

Objectives Children from different countries and with different ethnic backgrounds have a distinct pattern of central fat deposition. Therefore, it is essential to develop population-specific percentiles of waist circumference (WC), waist-to-height ratio (WHtR) and waist-to-height ratio exponent (WHtR (exp)) for the evaluation of central obesity. The objective of this study was to develop age-and-gender-specific smoothed WC and WHtR percentile curves for the Pakistani children and adolescents aged 2–18 years. Methods A cross-sectional data-set from a multi-ethnic anthropometric survey was considered. A sample of 10,668 healthy subjects (boys = 51.92%; and girls = 48.08%), aged 2–18 years was studied. Height (cm) and WC (cm) of each subject was measured under standard procedure and WHtR & WHtR (exp) were calculated. Age-and-gender-specific smoothed curves were obtained using the lambda-mu-sigma (LMS) method and compared with percentile curves obtained from different countries. Results Except few early ages, the WC values increased with age in both sexes. Both boys and girls had approximately similar WC during 6–11 years of age and after age of 11, the boys had larger WC than the girls had. For WHtR, the centile curves showed a continuous decrease by 16 years of age and then increased gradually. WHtR of the girls in various ages were having similar or higher than those of the boys. In comparison of WC 50th and 90th percentiles with other countries, it was found that except few ages, the Pakistani children had larger WC than the other reference populations and the results of WHtR were also comparable to the other nations. Conclusions We present new reference data of WC, WHtR and WHtR (exp) using a representative sample of the Pakistani children aged 2–18 years. These reference values can be used provisionally for early detection of central obesity and its associated risks in the Pakistani children.

Objectives The coexistence of celiac disease (CD) and obesity/overweight is not unusual. We investigate the prevalence and clinical presentation of CD, detected by screening, among children with excessive weight gain. Methods We enrolled 200 children referred for overweight/obesity to our outpatient clinic. Medical history during pregnancy and childhood and lifestyle variables were recorded. Patients were screened for CD with total immunoglobulin A (IgA), IgA anti-transglutaminase (tTG-IgA) and IgA anti-endomysial antibodies (EMA-IgA). In subjects with positive autoantibodies, esophagogastroduodenoscopy (EGDS) was performed and genetic testing for HLA DQ2 and/or DQ8 haplotypes was tested. Results CD positive antibodies (tTg-IgA and EMA-IgA) were detected in eight patients (4%); in all subjects CD diagnosis was confirmed by HLA-DQ2 and/or DQ8 compatibility and EGDS. No association between CD and medical history during pregnancy and childhood or lifestyle variables was noted; however, a dietary difference was identified with those testing positive for CD also reporting a lower weekly consumption of fruits and vegetables (p=0.04). Headache was reported more frequently in patients with than without CD (p=0.04). Familiar positivity for autoimmune diseases was revealed in CD patients (p=0.01). Conclusion CD should be considered in children with excessive weight gain. Familial predisposition to other autoimmune diseases may represent a risk factor for development of CD. Even though the relationship between headache and CD is not well defined, the patients with headache of unknown origin should be screened for CD.

Objectives Some factors in infancy can play a role in the development of adolescent obesity. Understanding these factors can help prevent early complications in adolescents associated with obesity in adulthood. The aim of this study was to determine the prevalence of overweight and obesity among high school girls in Khorramabad and its relationship with breastfeeding history. Methods This was a cross-sectional study. This study was conducted in 832 high school girls during the academic year 2016–2017. Samples were selected by multi-stage random sampling. General questionnaires, physical activity, and 24-h food questions were completed through interviews with students. Data regarding breastfeeding was obtained by mothers. Results The prevalence of overweight and obesity in the study population was 16.3 and 5.8%, respectively. Overweight and obesity had a significant association with breastfeeding history (p = 0.001), while there was no significant relationship between overweight and obesity with school type, student’s age, parental occupation, education Parents, household size, birth rate, physical activity, and energy intake. Conclusions The results of this study showed that breast feeding has a protective effect on overweight and obesity during adolescence. To reduce the incidence of overweight and obesity, necessary education regarding breastfeeding should be provided.

Objectives Patients with type-1 diabetes mellitus (T1DM) and celiac disease (CeD) share the same genetic susceptibility alleles. The diabetes-associated autoantibodies (DAA) may be detected in CeD patients. The aim of this study is to describe the prevalence of DAA in children with CeD. Methods This is a cross-sectional study of children with CeD. The CeD patients were divided into two groups; group 1 (n=23) included patients with isolated CeD and group 2 included patients with combined T1DM and CeD. The study was conducted at King Abdulaziz University Hospital (KAUH) in 2012–2014. DAA, including glutamic acid decarboxylase antibodies (GADA) and protein tyrosine phosphatase-2 antibodies (IA-2), were measured by enzyme-linked immunosorbent assay (ELISA) in both groups. Clinical, demographic, and laboratory data were collected from the patients’ medical charts. Results DAA were determined in 23 patients in group-1 and 18 patients in group-2. Group-1 comprised 43.5% males and 56.5% females; the mean age was 15 ± 3.7 years (with a range of 5–18 years). The prevalence of GADA and IA-2 was 69.6 and 4%, respectively. Group-2 comprised 55.6% males and 44.4% females; the mean age was 15.1 ± 2.8 years (with a range of 7–18 years). The prevalence of GADA and IA-2 was 66.7 and 22.2%, respectively. No significant differences were found between both groups in the prevalence of GADA (p=1.0) or IA-2 (p=0.15). Conclusions Saudi children with CeD have higher prevalence of GADA than reported in a number of other Western studies. Long-term follow-up data is required before recommending routine screening for DAA.

Objectives Endothelial dysfunction is an early marker of vascular disease in Type 1 diabetes mellitus (T1DM). In the present study, we aimed to investigate serum endocan and soluble endoglin (S-endoglin) levels, and their relation with metabolic control in children with T1DM, which was not previously assessed. Methods A total of 64 T1DM subjects and 64 healthy subjects were included in this study. Their anthropometric features, arterial blood pressures, pubertal status, insulin doses were recorded. Glycated hemoglobin, serum endocan and S-endoglin levels were measured and compared to each other. Results Serum endocan and S-endoglin levels were higher in children with T1DM than those of healthy group (p<0.01). Significant positive correlation was detected between both endocan and S-endoglin (r=0.579, p<0.001); and HbA1c and endocan (r=0.296, p=0.01). Compared to patients with good metabolic control, those with poorer metabolic control (HbA1c > 8%) had an older age, longer duration of diabetes, higher number of pubertal children. Also, patients with poorer metabolic control had higher endocan and S-endoglin levels than those of healthy group, but this finding did not reach statistical significance. There was no correlation between the endocan/S-endoglin levels and age, duration of diabetes and insulin dose. Conclusion Serum levels of endocan and S-endoglin which are novel biomarkers of endothelial dysfunction are high in children with T1DM. Elevated serum endocan and endoglin levels in children with T1DM without microvascular complications indicates endothelial damage in very early stages of the disease.

Objectives Congenital nephrogenic diabetes insipidus (NDI) is a rare hereditary disorder which is characterized by unresponsiveness to arginine vasopressin (AVP) in collecting ducts and leads to polyuria and polydipsia. The wide clinical spectrum of congenital NDI can cause difficulties in early diagnosis. We aimed to evaluate clinical prognosis of children with congenital NDI in long-term period. Methods Nineteen children with congenital NDI followed up in Pediatric Nephrology Department were enrolled to the study. This study is a single-center retrospective study, which reports clinical follow-up and genetic results of children with congenital NDI. Results Presenting symptoms of patients were mostly dehydration and fever due to polyuria and polydipsia. Four male patients had bilateral nonobstructive hydroureteronephrosis (HUN) and neurogenic bladder which requires clean intermittent catheterization (CIC). One patient had intracranial calcification which is a rarely seen complication in congenital NDI due to recurrent hypernatremic dehydration and severe brain dehydration. The causative mutations were identified in all patients. The identified mutations in six of them (31.6%) were hemizygous mutations in AVP R2 gene and homozygous mutations of AQP 2 gene in the rest 13 cases (68.4%). More than that, four of these mutations (two in AVP R2 and two in AQP 2) were novel mutations. Noncompliance with the treatments is associated with high risk of morbidity due to neurogenic bladder and chronic kidney disease (CKD). Conclusions The prognosis of congenital NDI is good when diagnosis can be made early and treatment is started immediately. Genetic counseling and prenatal testing for hereditary diseases are recommended especially in regions with relatively higher rates of consanguineous marriages.

Objectives The need for screening for autoimmune thyroid disease in children who have HLA-conferred susceptibility to type 1 diabetes (T1D), but have not yet been diagnosed with T1D, has not been thoroughly studied. The aim of this study was to describe the prevalence of positive thyroid peroxidase antibodies and its effect on thyroid function in children with genetic susceptibility to T1D as well as to describe the association between thyroid autoimmunity and HLA-DQ genotypes. Methods Cross-sectional study in 223 children (112 boys) aged 7.4–10.5 years with HLA-conferred susceptibility to T1D. TPOAb were measured in all children; thyroglobulin antibodies (TGAb) and thyroid function in TPOAb positive subjects. Results Girls had a significantly higher median TPOAb concentration than boys (12 vs 11 kU/L; p=0.001). Positive TPOAb occurred in 13.9% and positive TGAb in 4% of subjects. Only two children had mild changes in thyroid function. There was no association between HLA risk groups and the prevalence of TPOAb. Conclusions TPOAb are common in children with HLA-conferred susceptibility to T1D, yet are weakly associated with thyroid function, suggesting limited value of thyroid screening in this cohort.

Objectives The amount of Iodine-131 to treat young patients with differentiated thyroid cancer (DTC) has not been established so far. The purpose of this study was to perform and compare blood dosimetry by “Hanscheid’s approach”and lesion dosimetry by “Maxon’s approach”. Methods Seventy-one DTC patients ≤21 years were given diagnostic activity of 74 MBq 131 I followed by whole-body scan (WBS) at 2 h (pre-void), 24 h, 48 h, and ≥72 h. Pre-therapy blood and lesion dosimetry were conducted to determine the absorbed doses to blood and lesions and to predict the therapeutic activity. The administered activities were varied from 1.11–5.55 GBq of 131 I depending on disease extent. Post therapy dosimetries were again performed by acquiring WBS data at 24 h, 48 h, and ≥72 h. Results In blood dosimetry, the difference between predicted therapy activity (PTA) and actual therapeutic activity (ATA) was statistically significant in remnant and lung lesions but insignificant in nodal metastases (p=0.287). In lesion dosimetry, the difference between PTA and ATA was statistically significant for lung metastasis patients; however, not significant in remnant (p=0.163) and nodal metastases (p=0.054). The difference between predicted and observed absorbed dose was insignificant in blood dosimetry whereas, significant in lesion dosimetry. Conclusions The PTA based on 0.3 Gy recommendations of Hanscheid et al. may be adequate for patients with remnant or nodal metastases but inadequate for lung metastases. Lesion dosimetry demonstrated that there is scope to decrease the 131 I empiric ATA for remnant and nodal metastases; at the same time, there is scope to increase in lung metastasis patients.

Objective Mutations in the delta-like 1 homolog ( DLK1 ) gene have recently been reported in patients with idiopathic central precocious puberty (CPP). We aimed to investigate DLK1 mutations or polymorphisms in girls with CPP. Methods A total of 100 girls diagnosed with idiopathic CPP were enrolled. DLK1 coding regions were sequenced in girls with idiopathic CPP and healthy girls (controls). The relationship between identified sequence variations and CPP was evaluated via comparison of allele frequencies between patients with CPP and normal healthy controls. Results We identified five polymorphisms in DLK1 . There was no significant difference with regard to allele frequency between patients with CPP and controls. Polymorphism c.549C>T (p.G183G) in DLK1 gene was identified in only one patient with CPP. In silico analysis with human splicing finder suggested that the variant (c.549C>T) leads to splicing defect. Conclusions The sequencing of DLK1 gene has uncovered only one potentially meaningful variant. However, our results demonstrate that DLK1 mutations are a relatively rare cause of idiopathic CPP.

Objectives Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder, that could rarely be due to 17 α-hydroxylase deficiency (17αOHD) and/or 17,20 lyase deficiency. Mutation of CYP17A1 gene causes deficiency of glucocorticoids and androgens but excess of mineralocorticoids. Lack of genital ambiguity in most children causes a delay in diagnosis even until puberty. Classical presentation with hypertension and hypokalemia is often not encountered. We intended to study the clinical, biochemical and genetic characteristics of children diagnosed with CAH due to 17αOHD. Methods Three children who were diagnosed with CAH due to 17αOHD in our institute and on follow up were included in this retrospective study. Clinical, biochemical and genetic characteristics of these children were retrieved and studied from electronic medical records. Results Two children were genetic females and one was genetic male, but all three were raised as females. All had hypertension at diagnosis except one but none had hypokalemia. All of them had mutation in the CYP17A1 gene. The two females responded well to oestrogen and progesterone and had adequate estrogenization clinically. Conclusions Even though CAH due to 17αOHD is quite rare, it should be considered while evaluating young individuals with hypogonadism, hypertension with or without hypokalemia. Lack of genital ambiguity and absence of classical signs at presentation does not rule out this not so uncommon condition and warrants follow up.

Objective and methods To evaluate variation of capillary phenylalanine concentrations over the day in patients treated for phenylketonuria and the reliability of the morning sample to assess metabolic control, we conducted a repeated cross-sectional study in 25 Tunisian patients on phenylalanine-low diet. For each patient, we collected nine capillary samples over the day. Phenylalanine was dosed by fluorimetry. Results There was a wide variability of phenylalanine concentrations over the day (p<0.001). Compared to morning sample, phenylalanine concentration was significantly lower before lunch (p=0.038), after lunch (p=0.025), before dinner (p<0.001), after dinner (p=0.035) and at 4:00 a.m. (p=0.011). Compared to the 24 h sampling, the morning sample had a 68% to identify unbalanced patients. 60% of patients, had peak phenylalanine concentration after the morning. Half of the patients with normal morning phenylalanine concentration had low phenylalanine values over 8–20 h. Percentages of high phenylalanine concentrations over the last semester were higher in patients with poor metabolic control over the 24 h (21% ± 43 vs. 0% ± 9%); p=0.043. Conclusion A single morning sample gives an incomplete information on metabolic control in phenylketonuric patients. Using four pre-prandial samples on the day should be considered as alternative in patients with good metabolic control.

Objectives Phosphate is essential for skeletal mineralization, which is regulated by parathyroid hormone, calcitriol and fibroblast growth factor 23 (FGF23). Serum phosphate is physiologically higher in younger children, but factors that contribute to this physiological state are poorly understood. This study aimed to evaluate phosphate and its regulators in children compared with adults. Materials and methods The participants were children aged 3–11 years and adults older than 20 years of age. Biochemical parameters including calcium, phosphorus, alkaline phosphatase, FGF23, and vitamin D were measured. Fractional excretion of phosphate was calculated, using serum and urine phosphate and creatinine. Results This cross-sectional study was conducted on 45 children (mean age: 9.0 ± 2.1) and 44 adults (mean age: 38.9 ± 11.1). The children had higher serum calcium, phosphate, alkaline phosphatase, and FGF23 (p < 0.001), but fractional excretion of phosphate was greater in adults (14.1 ± 5.7, 11.4 ± 4.4, p = 0.019, 95% confidence interval [CI]: −0.7 to −0.2). Of all individuals, 61.8% had vitamin D deficiency. By multiple regression analysis, entering age, calcium, phosphate, and vitamin D level, the only independent predictor of FGF23 was 1, 25 dihydroxy-vitamin D3 ( β : 0.78, p < 0.001, 95% CI: 0.5–1.1, R 2 : 0.59 for children, and β : 0.59, p < 0.001, 95% CI: 0.5–1.4, R 2 : 0.45 for adults). Conclusion As far as we know, there is little information regarding the role of FGF23 in physiologic state. In this cross-sectional study no association was found between FGF23 and urinary phosphate excretion in growing children. Further studies with more detail are essential to evaluate phosphate homeostasis during childhood.

Objectives Basal (unstimulated) LH levels and leuprolide stimulation tests are used to define pubertal status of children presenting with signs of early puberty. The primary aims of this study were to (i) confirm utility of detectable basal LH levels in precluding the need for leuprolide stimulation testing, and, (ii) determine whether duration of testing could be abbreviated from usual 3 h test without compromising sensitivity. Methods We reviewed morning basal and leuprolide-stimulated LH levels in 105 children, aged 1–9 years (mean 6.9 years, SD 1.8) who were seen for concerns of precocious puberty and received a leuprolide stimulation test between June 2006 and March 2017. Results A pubertal basal LH level had high specificity and poor sensitivity for the following outcome measures: (1) peak stimulated LH≥5 mIU/mL (2) treatment with GnRHa; and (3) a composite outcome of (1) and/or (2). Following leuprolide stimulation, LH response was highest at 180 min in most children (n=78, 74.3%). Using a single cutoff of LH≥5 mIU/mL at any timepoint, 25% of children would have been misdiagnosed with an abbreviated 60 min test. A single sample at 180 min would have correctly identified 97% of patients. Conclusions A pubertal basal LH level is sufficient to distinguish children with precocious puberty without stimulation testing. However, prepubertal basal LH had relatively poor negative predictive value to refute CPP, necessitating clinical follow-up and/or a leuprolide stimulation test. For a cutoff of LH≥5 mIU/mL at any timepoint, test duration of 180 min maximizes sensitivity.

Objectives In children with cerebral palsy (CP), the most common cause of physical impairment in childhood, less muscle and bone growth has been reported, when compared with typically developing children. The aim of this study was to evaluate the effect of an intensive rehabilitation program including physiotherapy in combination with 6 months of home-based, vibration-assisted training on muscle and bone growth in children with CP. Methods We included children with CP, who participated in a rehabilitation program utilizing whole-body vibration (WBV). Muscle mass was quantified by appendicular lean mass index (App-LMI) and bone mass by total-body-less-head bone mineral content (TBLH-BMC) assessed by Dual-energy X-ray absorptiometry (DXA) at the beginning of rehabilitation and one year later. To assess the functional muscle-bone unit, the relation of TBLH-BMC to TBLH lean body mass (TBLH-LBM) was used. Results The study population included 128 children (52 females, mean age 11.9 ± 2.7). App-LMI assessed in kg/m2 increased significantly after rehabilitation. The age-adjusted Z -score for App-LMI showed no significant change. TBLH-BMC assessed in gram increased significantly. The Z -scores for TBLH-BMC decreased lesser than expected by the evaluation of the cross-sectional data at the beginning of rehabilitation. The parameter T B L H − B M C T B L H − L B M $\frac{TBLH-BMC}{TBLH-LBM}$ did not change relevantly after 12 months. Conclusions Muscle growth and to a lesser extent bone growth could be increased in children with CP. The intensive rehabilitation program including WBV seemed to have no direct effect on the bone, but the observed anabolic effect on the bone, may only been mediated through the muscle.

Objectives To present a case report of succesfully metyrapone treatment of a neonatal patient with McCune–Albrigth syndrome (MAS), a rare disease caused by a genetically mosaic disorder and is characterized by variable hyperfunctional endocrinopathies, bone dysplasia, and café-au-lait spots. Case presentation A preterm newborn was admitted to hospital and she presented difficulty controlling hypertension, café-au-lait spots, and failure to thrive. An abdominal ultrasound and a magnetic resonance showed a high volume of both suprarenal glands. Therefore, MAS was suspected. Laboratory data confirmed adrenocorticotropic hormone-independent Cushing’s syndrome with hepatic dysfunction and metyrapone treatment was initiated. A progressive normalization of cortisol levels was achieved despite poor oral tolerance. Conclusion Our case shows that metyrapone is useful in the management of neonatal Cushing’s syndrome due to McCune–Albright syndrome.

Objectives We report a case of pediatric thoracic tumor-induced osteomalacia (TIO) causing severe hypophosphatemic rickets with delayed diagnosis and emphasize on timely management of this rare entity. Case presentation A young boy presented with rickets since five years of age. Biochemical evaluation revealed hypophosphatemia, hyperphosphaturia, elevated alkaline phosphatase and normal calcium levels. Initially managed as hereditary hypophosphatemic rickets, he was given phosphorus supplements and calcitriol. Despite the therapy, skeletal deformities worsened requiring surgical corrections. Subsequently, he developed iatrogenic tertiary hyperparathyroidism for which he underwent total parathyroidectomy. Later on, he was found to have fibroblast growth factor-23 secreting thoracic mass (10.5 cm in largest dimension) which was excised with significant post operative improvement. Histopathology showed phosphaturic mesenchymal tumor-mixed connective tissue variant, confirming the diagnosis of TIO. Conclusion TIO, a correctable cause of hypophosphatemic rickets, should be considered in children presenting with hypophosphatemic rickets with evident mass on examination/imaging and in refractory cases.

Objectives The main cause of hyperandrogenism in children is congenital adrenal hyperplasia, adrenal and gonadal tumors, polycystic ovary syndrome (PCOs) and Cushing’s disease. In the last 20 years several descriptions of girls with hyperandrogenism and venous porto-systemic shunts appeared in literature. Case presentation First case is an eleven and a half-year-old girl, was admitted to Department of Endocrinology because of symptoms of hyperandrogenism. Laboratory tests revealed high serum testosterone, androstenedione, and dehydroepiandrosterone sulfate (DHEAS). The ammonia concentration was also increased. In the abdominal angio-CT scans persistent umbilical vein which connected portal and femoral vein was found. The second case was a seven-year-old boy with symptoms of precocious puberty. Blood tests also revealed high concentration of testosterone, androstenedione, DHEAS and ammonia. Imaging studies showed persistent ductus venosus. Conclusion Although pathophysiological relation is not clear, porto-systemic shunts should be considered as a cause of hyperandrogenism of unknown origin in children.

Objectives Vitamin A is essential for normal cellular physiology and is often taken as a dietary supplement. Hypervitaminosis A can lead to hypercalcemia by increasing osteoclasts and subsequent bone resporption. Dietary supplements including vitamin A are new popular treatment stategies for autism. Case presentation We report a five-year old boy with autism spectrum disorder presenting with severe abdominal pain and bilateral lower extremity pain, who was found to have persistent hypercalcemia due to hypervitaminosis A. The patient ingested over 700 times the recommended intake of Vitamin A per day for age. Retention of vitamin A in the liver and adipose tissue causes toxic levels of retinoids and hypercalcemia. Conclusions Acute treatment included intravenous rehydration, furosemide, and calcitonin. Pamidronate was the definitive treatment for hypercalcemia from hypervitaminosis A due to its osteoclast inhibition and long biologic half-life. Parents should be counseled on risks of toxicity and absence of evidence showing benefits of vitamin A therapy for autism.