Band 29, Heft 8

Background: Osteocalcin (OC) is a bone-specific protein secreted by osteoblasts and often used as a bone formation biomarker. OC undergoes post-translational carboxylation to yield carboxylated osteocalcin (Gla-OC) and undercarboxylated osteocalcin (uc-OC) molecules. The aim of this study was to explore the association between bone and glucose metabolism by evaluating OC, ionized cations, and markers of glucose metabolism in children with obesity and type 2 diabetes mellitus (DM2). Methods: The subjects were nine children with DM2 [six males, three females; age 15.7±4.1 years; duration of disease 3.2±1.2 years], 18 children with simple obesity [12 males, six females; age 12.6±4.1 years], and 12 controls [eight males, four females; age 12.3±3.2 years]. Serum Gla-OC and uc-OC levels were determined using an enzyme-linked immunosorbent assay (ELISA). Results: Patients with DM2 (0.65±0.46 ng/mL), but not with obesity (1.11±0.55 ng/mL), had lower uc-OC levels than controls (1.25±0.49 ng/mL). Serum uc-OC was negatively correlated with mean serum glucose levels (r=–0.447, p=0.013) and hemoglobin A1c (HbA 1c ) (r=–0.455, p=0.012) in all subjects. Serum Gla-OC was correlated with serum alkaline phosphatase (r=0.601, p<0.001) and inorganic phosphorus (r=0.686, p<0.001), yet negatively correlated with age (r=–0.383, p=0.030). Mean serum ionized magnesium was lower in DM2 subjects than in controls. Mean serum ionized calcium was higher in obese subjects than in controls. In all subjects, mean serum ionized magnesium was negatively correlated with mean serum glucose levels. Conclusions: Osteoblast-derived protein OC, especially uc-OC, may have a role in the pathophysiology of diabetes by being associated with blood glucose homeostasis.

Background: The aim of the study was the evaluation of the effects of glycemic control in children and adolescents with type 1 diabetes on cardiac functions. Methods: Diabetic patients were divided into two groups as well-controlled and poorly controlled patients. All patients underwent M-mode, two-dimensions (2D), pulsed wave (PW) Doppler, and tissue Doppler (TDI) echocardiography to evaluate systolic and diastolic functions. Results: Early diastolic mitral flow velocity (Em) and the ratio of early to late diastolic mitral flow velocity (Em/Am) obtained with TDI were found to be significantly lower in the well-controlled then the control group and significantly lower in the poorly-controlled group than the well-controlled group. Am, isovolumetric relaxation time (IVRT) and myocardial performance index (MPI) were significantly higher in the poorly controlled group. The ratio of early mitral diastolic flow velocity obtained with PW Doppler (E) to Em (E/Em) was significantly higher in the diabetic group. According to the mitral valve PW Doppler results, 13.6% of the well-controlled group and 31% of the poorly-controlled group had type 1 diastolic dysfunction. According to the mitral TDI results, 18% of the well-controlled group and 40.4% of poorly-controlled group had type 1 diastolic dysfunction. Conclusions: Conventional and TDI echocardiography revealed impairment in left ventricular functions in some patients. Tissue Doppler echocardiography also revealed diastolic impairment in some patients who appeared normal with PW Doppler echocardiography. The present study found that impairment in left ventricular diastolic functions is directly related to glycemic control and the rate of diabetic cardiomyopathy was higher in children with poor metabolic control.

Background: Children with type 1 diabetes mellitus (T1DM) are on intensive treatment regimen with the stress of maintaining normal sugars which may predispose them to psychological problems. The study aimed to assess the prevalence of psychosocial problems and to study their correlates in children with T1DM in India. Methods: The study was conducted on 97 T1DM children (59 boys and 38 girls) between 4 and 15 years of age with at least 6 months of illness. Psychosocial problems were assessed using childhood psychopathological measurement schedule (CPMS) questionnaire. Information regarding glucose control and various demographic factors was recorded. Factors significantly associated with psychosocial problems were further analysed using multiple linear regression. Results: Mean age of patients was 9.6 years. The prevalence of psychosocial problems was found to be 20%. Most common problems were conduct disorders (24.5%), special symptoms (24%), physical illness (23%), anxiety (10%) and depression (7%). Depression had the strongest correlation (r=0.316 and p=0.002) with glycosylated haemoglobin (HbA 1c ), followed by behavioural problems/low intelligence (r=0.236 and p=0.02). CPMS score had a strong positive correlation with number of hyperglycaemic episodes, number of hospitalisations in last 6 months and HbA 1c value. HbA 1c over last 6 months and total number of hospitalisations were significant independent predictors in determining psychosocial problems. Conclusions: Psychosocial problems were seen in 20% children with T1DM from India. Poor glycaemic control and increased number of hospitalisations are significantly associated with increased psychosocial problems in T1DM.

Background: Gastrointestinal hormones, such as glucagon-like peptide (GLP-1), have been hypothesized to play a role in the pathogenesis of obesity-related complications. However, few data are available in youth. The objective of this study was to investigate the GLP-1 response to oral glucose load in obese pre-pubertal children and its relationship with insulin secretion. Methods: Ten pre-pubertal obese children [five boys; 10.5±1.6 years; body mass index-standard deviation score (BMI-SDS): 2.2±0.5] and 10 controls (eight boys; 9.9±1.2 years; BMI-SDS: –0.7±0.5) underwent a modified oral glucose tolerance test (OGTT) to evaluate post-load glucose, insulin and GLP-1 responses. Insulin sensitivity [homeostasis model assessment of insulin resistance (HOMA-IR), whole body insulin sensitivity index (WBISI)] and secretion [HOMA-beta, insulinogenic index (IGI)] indexes, area under the curve (AUC) for glucose, insulin and GLP-1 were calculated. Results: In obese children GLP-1 AUC values were higher and correlated with BMI-SDS (r=0.45; p=0.04), HOMA-IR (r=0.53; p=0.01) and fasting glucose (r=0.68; p=0.001). Conclusions: Obese children showed an increased GLP-1 response to oral glucose. These changes might likely represent a compensatory mechanism to avoid post-prandial hyperglycemia and allow a normal glucose tolerance.

Background: Idiopathic intracranial hypertension (IIH) is one of the most important and rare complications of obesity. Prevalence of IIH in childhood obesity is not known. The purpose of this study was to determine the prevalence of IIH in obese children and adolescents and to investigate the relevant factors. Methods: In this study, 1058 obese children and adolescents between 2 and 18 years of age were included. Funduscopic examination was conducted for all subjects. In cases with papilledema, increase in intracranial pressure was clarified by measuring CSF pressure with a lumbar puncture. Other causes of IIH were ruled out with clinical, laboratory tests and imaging techniques. Results: Idiopathic intracranial hypertension was diagnosed in 14 subjects (1.32%). Rates of headache and systemic hypertension in subjects with IIH was determined to be 78.6% and 28.6%, respectively. Morning cortisol, fasting insulin and HOMA-IR values were found to be significantly higher in this cases (p<0.05). Conclusions: In childhood obesity, IIH should be kept in mind as a serious complication. Funduscopic examination is an easy method that suggests IIH. In particular, obese children with systemic hypertension and refractory headache should be considered for IIH.

Background: Idiopathic postprandial hyperinsulinaemic hypoglycaemia (PPHH) has rarely been reported in the paediatric age. The objective of this study was to describe the clinical characteristics, diagnosis and management in a group of children with PPHH. Methods: Six children (three females) with a mean follow-up of 3.5±3.0 years at a single tertiary paediatric hospital. All had 24-h blood glucose monitoring, diagnostic fast and prolonged oral glucose tolerance test (OGTT). Follow-up included: 24-h blood glucose monitoring or continuous glucose monitoring system, prolonged OGTT and/or mixed meal (MM) test. Results: Age at diagnosis ranged from 5.4 to 15.7 years and auxology parameters were within normal range in all subjects. All the children had a normal fasting tolerance for age. Prolonged OGTT demonstrated symptomatic hypoglycaemia after 120 min in all the patients with simultaneous detectable serum insulin concentration. Acarbose was tried in three patients, having a positive effect on glycaemic and symptom control, but due to side effects, only two patients continued acarbose in the long run. Diazoxide proved to be beneficial in one patient. The rest of the patients were managed with frequent feeds but despite this, prolonged OGTT/MM demonstrated on-going PPHH. Conclusions: Prolonged OGTT is necessary to diagnose PPHH in children. Acarbose is beneficial in children with PPHH, although not well tolerated. Patients managed exclusively on frequent feeds demonstrated persistent hypoglycaemia on OGTT. The underlying cause of the PPHH in these patients remains unknown.

Background: Although most individuals with Prader-Willi syndrome (PWS) are obese, little is known about the impact of obesity-related psychosocial factors in PWS. In the present study we compared feeding, eating, and behavioral disturbances in children and adolescents with PWS, peers with non-syndromal obesity, and normal weight controls. Methods: Twelve persons with PWS, aged 7–22 years, age- and gender-matched obese and normal weight individuals were analyzed regarding parental feeding practices, eating disturbances, and behavioral problems via standardized questionnaires. Results: Parents of individuals with PWS reported significantly more restrictive feeding and monitoring than did parents of obese or normal weight children without PWS (p<0.05). Social problems were more common in the obese and the PWS group than in the normal-weight group (p<0.05). Behavioral problems were significantly correlated with parental restrictive feeding practices. Conclusions: Our data show that children and adolescents with PWS are affected by psychosocial problems, and that restrictive feeding practices might be associated with more severe behavioral problems. Further studies in larger samples will be necessary to replicate these results and possibly provide new therapeutic approaches for the management of PWS.

Background: This study aimed to determine the strain index (SI) of normal thyroid parenchyma in a group of healthy children, using ultrasound elastography (USE). Methods: The participants consisted of 54 healthy children. The USE of the normal thyroid parenchyma was performed by using the Hitachi Hi VisionPreirus model ultrasonography (US) device. By following sinusoidal waves at the base of the screen, regular and slight compressions and decompressions were made by the transducer. After the regular sinusoidal waves were acquired, standard region of interest (ROI) circles were used to measure the SI values of the thyroid glands by placing one ROI on a superficial part of the normal thyroid gland parenchyma and the other on the adjacent soft tissue at the same depth (within 10-mm proximity). Three measurements were obtained for each (right and left) thyroid gland, and the mean value was used for statistics. Results: The mean SI value of normal thyroid glands was 0.54±0.38 for the whole group. There was no statistically significant difference between girls and boys on the basis of age, weight, height, BMI (body mass index), and thyroid SI values (p=0.15, p=0.18, p=0.12, p=0.31, and p=0.96, respectively). No correlation was found between thyroid gland SI values and each of the following variables: age (r=0.22, p=0.15), gender (r=0.007, p=0.96), and BMI (r=0.26, p=0.09). Conclusions: The study determined the normal elasticity values of thyroid glands in healthy children. Such information can serve as a baseline from which thyroid diseases can be examined.

Background: In children born small for gestational age (SGA) with catch-up growth, a higher risk of insulin resistance (IR) and cardiovascular diseases is noted. Ghrelin stimulates a growth hormone (GH) secretion and regulates lipid and carbohydrate metabolism. We assessed gherlin’s influence on achieving normal height and the occurrence of metabolic complications in SGA children. Methods: Ghrelin, insulin-like growth factor type I (IGF-I), leptin, adiponectin, resistin, glucose, insulin and lipid concentrations were analysed in 134 prepubertal children in four groups: normal-height SGA, short SGA, normal-height born appropriate for gestational age (AGA) and short AGA. Results: Ghrelin and IGF-I concentrations were significantly higher while adiponectin – lower in normal-height SGA comparing to others. Conclusions: The increased production of ghrelin and IGF-I seems to be an adaptive mechanism to achieve normal growth in SGA children. The significance of high ghrelin and low adiponectin concentrations, observed in normal-height prepubertal SGA children, requires elucidation, with reference to the development of metabolic complications.

Background: The advent of bisphosphonates (BPs) has revolutionised the outcome of Osteogenesis imperfecta (OI) in the last few years. There has always been a safety concern regarding zoledronate’s use due to a paucity of studies. The current study is a retrospective evaluation of children with OI on the short- and long-term side effects of zoledronate and the frequency of fractures per year after the drug was introduced. Methods: A total of 26 children diagnosed with OI, with a median age of 84 (45–121) months were enrolled in the study. They received cyclical zoledronate for a median duration of 36 (11–61) months at quarterly intervals between January 2008 and December 2014. Safety evaluation involved assessment of its short- and long-term effects in addition to the frequency of fractures after its usage. Results: One (3%) neonate had symptomatic hypocalcemia 15 days after the infusion. Three children (11%) had acute phase reactions. None had long-term side effects, including osteonecrosis of the jaw, in our 7-year experience. OI of types III and IV (total of 22) had significant reductions in the number of fractures (p<0.05). Conclusions: Further long-duration studies are necessary to evaluate the longterm safety of zoledronate.

Background: There is evidence that iron affects lipid metabolism and adipocyte biology. Given the effects of iron on adiponectin, the role of iron in lipid oxidation, and the potential additive effects of oxidative stress from excess iron and lipid metabolism. We aimed to investigate serum adiponectin in relation to clinical and laboratory parameters including the inflammation markers [C-reacitve protein (CRP) and interleukin-6 (IL-6)] in β-thalassaemia major children. Methods: We investigated 58 β-thalassaemia major children under scheduled blood transfusion and 30 controls. Routine clinical evaluation, laboratory investigations including serum ferritin as well as CRP measured by immunoturbidimetry, IL-6 and serum adiponectin measured by ELISA are performed. Results: CRP, IL-6 and serum adiponectin levels were higher in patients than controls (p<0.001, p=0.04 and p<0.001, respectively). Patients received desferoxamine showed significantly lower levels of adiponectin than those did not receive it (mean±SD=4.50±3.37 vs. 9.96±9.68, p=0.006). Serum adiponectin was significantly negatively correlated with hemoglobin (Hb) concentration (r=–0.36, p=0.005). It was significantly positively correlated with platelets count, serum ferritin, CRP and IL-6 (r=0.27, r=0.26, r=0.30, r=0.35, respectively and p=0.04, p=0.04, p=0.01, p=0.008, respectively). Serum ferritin and IL-6 were the significant predictors of serum adiponectin level (p<0.001 and p=0.003, respectively). Conclusions: Serum adiponectin was increased in β-thalassaemia major as were pro-inflammatory markers (CRP and IL-6). Its level is directly associated with ferritin and IL-6 levels.

Background: Maturity-onset diabetes of the young type 2 (MODY2) is caused by mutations in the glucokinase ( GCK ) gene and is rare in the Chinese population. We report three Chinese families with MODY2 and the sequencing of the GCK gene. Methods: Three unrelated Chinese families with MODY2 and their pedigrees were investigated. In Family 1, the proband was a 7-year-old girl with impaired fasting glucose (IFG) and impaired glucose tolerance (IGT). Her mother and maternal grandfather had IFG. In Family 2, the proband was a boy who had diabetes mellitus at 11 years. His sister had IFG. His father and grandmother had diabetes mellitus at 22 and 25 years, respectively. In Family 3, the proband was a boy who had IFG and IGT at 12 years. His sister had diabetes mellitus at 8 years. His father and grandfather had IFG and/or IGT. The GCK gene was directly sequenced. Results: Diabetes mellitus or IFG/IGT was found among three consecutive generations in three families. One novel nonsense heterozygous mutation in exon 5 (c.556 C>T, p.Arg 186 stop) was detected in Family 1. Another novel frameshift mutation in exon 4 (c.367-374dupTTCGACTA, p.Ile 126 fs) was found in Family 2. A previously reported, a missense heterozygous mutation in exon 5 (c.571 C>T, p.Arg 191Trp) was detected in Family 3. Conclusions: The thorough investigation of three Chinese families with MODY2 revealed two novel mutations and one known mutation. GCK gene sequencing helps in MODY2, especially when there is uncertain IFG or IGT.

Background: This study was conducted to investigate CTNS (cystinosin, lysosomal cystine transporter) gene mutations and the clinical spectrum of nephropathic cystinosis among patients diagnosed with the disease in a single center in Turkey. Methods: Patients’ clinical and laboratory data were extracted from an electronic health registry. Molecular CTNS gene analysis was performed using either next-generation sequencing or Sanger sequencing. Results: Eleven patients (age range: 1.5–12 years) from nine families were identified. The presenting complaint was growth retardation in seven patients; polydipsia and polyuria in three patients; and vomiting in two patients. At presentation, electrolyte loss was noted in all patients, of which eight patients presented with metabolic acidosis, and three patients presented with metabolic alkalosis. All patients also presented with proteinuria and glucosuria, and four patients developed varying degrees of renal insufficiency, for which peritoneal dialysis was initiated in one patient. Cystine crystals were detected via ocular examination in one patient at presentation. No cystine crystals were detected among patients who underwent bone marrow aspiration. In the CTNS gene, a p.T7FX7 (c.18-21del4bp) mutation was detected in three patients, whereas a p.E227E (c.681 G>A) (homozygous) mutation was detected in eight patients. Conclusions: We detected two distinct mutations, p.T7FX7 (c.18-21del4bp) and p.E227E (c.681 G>A) (homozygous), in the CTNS gene in 11 patients with cystinosis from the East Anatolian region of Turkey. Patients with a homozygous c.681 G>A (p.E227E) mutation are more likely to develop chronic renal failure and should be monitored closely, whereas patients with a p.T7FX7 (c.18-21del4bp) mutation have a milder phenotype. Additionally, metabolic alkalosis does not exclude cystinosis, although cystinosis is a cause of proximal renal tubular acidosis.

Background: Microarray technology has been used to analyze gene expression in patients with and without slipped capital femoral epiphysis (SCFE). Methods: Proximal femoral physis core biopsies from two patients with SCFE were compared with two control specimens from age-matched patients without SCFE. Extracted RNA from frozen ground samples was subjected to microarray analysis with data tests for statistical significance between SCFE and control tissues. Results: Compared to controls, SCFE samples demonstrated significant up-regulation in gene expression pathways involving physiological defense and inflammatory responses and significant down-regulation in the regulation of cellular physiologic processes, cellular metabolic pathways, and skeletal development pathways including expression of aggrecan and type II collagen, genes affecting physeal structure and integrity. Conclusions: Up-regulation of inflammatory and immune response pathways in SCFE compared to controls relates to physeal mechanical displacement in SCFE. Globalized down-regulation of several other pathways suggests growth plate weakening. These novel microarray findings further define SCFE etiology.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), also named as autoimmune polyglandular syndrome (APS) type 1, is a rare autosomal recessive disorder caused by mutations in autoimmune regulator ( AIRE ) gene. It is distinguished by an immune-mediated damage of endocrine tissues, chronic candidiasis, and ectodermal disorder. APECED has been shown to be frequent in some populations including Iranian Jews. Here we report three cases of APECED from two independent Iranian Muslim families. Addison’s disease, hypoparathyroidismand mucocutaneous candidiasis were shared clinical manifestations in all patients. Mutational analyses have demonstrated a novel homozygous splice site mutation (c.1095+2T>A) in intron 9 and a previously identified homozygous nonsense mutation (c.415C>T) in exon 3 of patients respectively. Future studies are needed to evaluate the frequency of these variants in Iranian APECED patients which would facilitate genetic counseling as well as prenatal diagnosis.

Limbic encephalitis is a rare neurological disorder that may be difficult to recognize. Clinical features include memory impairment, temporal lobe seizures and affective disturbance. We report the case of a 10-year-old girl with type 1 diabetes mellitus that presented with seizures, depressed mood and memory changes. The diagnosis of glutamic acid decarboxylase 65 (GAD65) mediated limbic encephalitis relied on cerebral magnetic resonance imaging lesions and high serological and cerebrospinal fluid GAD65-antibodies titers. High-dose steroidal therapy was started with clinical improvement. Relapse led to a second high-dose steroid treatment followed by rituximab with remission. A correlation between serum GAD65-antibodies levels and symptoms was found, demonstrating GAD65-antibodies titers may be useful for clinical follow-up and immunotherapy guidance. This report raises awareness of this serious neurological condition that may be associated with type 1 diabetes, underlining the importance of an early diagnosis and prompt treatment for a better prognosis.

Mucolipidosis type II α/β (ML II α/β) and mucolipidosis type III α/β (ML III α/β) have been shown to be caused by an absence or reduced level of uridine diphosphate (UDP)-N-acetylglucosamine-1-phosphotransferase enzyme (EC 2.7.8.17) activity, respectively. Both disorders are caused by mutations in the GNPTAB gene and are inherited in an autosomal recessive manner. Here we report a 2-year-old female patient being diagnosed as a case of ML II α/β due to coarse face, severe developmental delay, multiple dysostosis, noticeable increase of multiple lysosomal enzymes activity in plasma and normal acid mucopolysaccharides in urine. Mutational analysis of the GNPTAB gene has revealed a novel homozygous mutation in the patient (c.3250-2A>G) with both parents being heterozygote. Transcript analyses showed that this novel splice site mutation leads to exon 17 skipping and a frameshift afterwards (p.P1084_R1112del F1113Vfs*1). Consequently, we confirmed the association of this mutation with ML II α/β. Our finding expands the number of reported cases of this rare metabolic disorder and adds to the GNPTAB mutation database.

Social and emotional impairment, school dysfunction, and neurobehavioral impairment are highly prevalent in survivors of childhood craniopharyngioma and negatively affect quality of life. As surgical resection of craniopharyngioma typically impairs hypothalamic/pituitary function, it has been postulated that perhaps post-operative deficiency of the hormone oxytocin may be the etiology of social/emotional impairment. Research on the benefits of oxytocin treatment as a hormone facilitating social interaction is well established. However, no research has yet been conducted on patients with known pituitary/hypothalamic dysfunction due to structural lesions or surgery. This case report investigates the effects of oxytocin therapy on a youngster with pituitary/hypothalamic dysfunction after craniopharyngioma removal. In this individual, treatment with low dose intranasal oxytocin resulted in increased desire for socialization and improvement in affection towards family. In light of these findings, the authors believe that further research into the potential benefits of intranasal oxytocin therapy for patients with panhypopituitarism is necessary to determine whether a broader population may also benefit from intranasal oxytocin therapy.

Diabetic ketoacidosis (DKA) is a complex metabolic state characterized by hyperglycemia, metabolic acidosis and ketonuria. Cerebral edema is the most common rare complication of DKA in children. The objective of the study was to emphasize the importance of careful evaluation and monitoring for signs and symptoms of cerebral edema in all children undergoing treatment for DKA. We present a case of 11-year-old girl with a history of diabetes mellitus type I (T1DM) who presented with severe DKA complicated by hypovolemic shock, cerebral edema and hematemesis. Considering the fact that complications of DKA are rare and require a high index of clinical suspicion, early recognition and treatment are crucial for avoiding permanent damage.