Band 30, Heft 10

Background: Growth prediction models (GPMs) exist to support clinical management of children treated with growth hormone (GH) for growth hormone deficiency (GHD), Turner syndrome (TS) and for short children born small for gestational age (SGA). Currently, no prediction system has been widely adopted. Content: The objective was to develop a stand-alone web-based system to enable the widespread use of an ‘individualised growth response optimisation’ (iGRO) tool across European endocrinology clinics. A modern platform was developed to ensure compatibility with IT systems and web browsers. Seventeen GPMs derived from the KIGS database were included and tested for accuracy. Summary: The iGRO system demonstrated prediction accuracy and IT compatibility. The observed discrepancies between actual and predicted height may support clinicians in investigating the reasons for deviations around the expected growth and optimise treatment. Conclusions: This system has the potential for wide access in endocrinology clinics to support the clinical management of children treated with GH for these three indications.

Background: Childhood obesity may lead to neuronal impairment in both the peripheral and the central nervous system. This study aimed to investigate the impact of obesity and insulin resistance (IR) on the central nervous system and neurocognitive functions in children. Methods: Seventy-three obese children (38 male and 35 female) and 42 healthy children (21 male and 21 female) were recruited. Standard biochemical indices and IR were evaluated. The Wechsler Intelligence Scale for Children-Revised (WISC-R) and electroencephalography (EEG) were administered to all participants. The obese participants were divided into two groups based on the presence or absence of IR, and the data were compared between the subgroups. Results: Only verbal scores on the WISC-R in the IR+ group were significantly lower than those of the control and IR– groups. There were no differences between the groups with respect to other parameters of the WISC-R or the EEG. Verbal scores of the WISC-R were negatively correlated with obesity duration and homeostatic model assessment-insulin resistance (HOMA-IR) values. EEGs showed significantly more frequent ‘slowing during hyperventilation’ (SDHs) in obese children than non-obese children. Conclusions: Neurocognitive functions, particularly verbal abilities, were impaired in obese children with IR. An early examination of cognitive functions may help identify and correct such abnormalities in obese children.

Background: Along with increased prevalence of obesity, body weight misperception has also increased among adolescents. This study aims to evaluate the proportion of weight misperception among Iranian children and adolescents and its association with some health-related factors. Methods: Data were collected from 14,440 Iranian students, aged 7–18 years, who participated in the national school-based surveillance program (CASPIAN-V). The students’ anthropometric indices and blood pressure were measured using standardized methods, and valid questionnaires were used to assess their weight perception, eating patterns, physical activity and sedentary behaviors. According to agreements between the real weight and self-perceived weight status, participants were classified as underestimated, accurate and overestimated weight. Results: The rates of underestimated, accurate and overestimated weight were 30.8%, 40.8% and 28.4%, respectively. In comparison with the accurate-weight group, both the underestimated- and overestimated-weight groups were less likely to have daily consumption of sugar-sweetened beverages (OR: 0.83, 95% CI: 0.74–0.93 and OR: 0.39, 95% CI: 0.34–0.44, respectively), sweets (OR: 0.81, 95% CI: 0.73–0.90 and OR: 0.68, 95% CI: 0.61–0.76, respectively) and salty snacks (OR: 0.78, 95% CI: 0.66–0.92 and OR: 0.30, 95% CI: 0.24–0.38, respectively). In the overestimated-weight group, the odds of daily intake of fast food decreased by 67% and the odds of low physical activity declined by 38% in comparison with the accurate-weight group. Conclusions: Weight misperception had a high prevalence among Iranian children and adolescents and is associated with their dietary patterns and physical activity behaviors. Suitable education programs need to be developed to correct the children and adolescents’ insight about their weight status.

Background: The changes in serum 25-hydroxyvitamin D (25(OH)D) in adolescents from summer to winter and optimal serum vitamin D levels in the summer to ensure adequate vitamin D levels at the end of winter are currently unknown. This study was conducted to address this knowledge gap. Methods: The study was conducted as a cohort study. Sixty-eight participants aged 7–18 years and who had sufficient vitamin D levels at the end of the summer in 2011 were selected using stratified random sampling. Subsequently, the participants’ vitamin D levels were measured at the end of the winter in 2012. A receiver operating characteristic (ROC) curve was used to determine optimal cutoff points for vitamin D at the end of the summer to predict sufficient vitamin D levels at the end of the winter. Results: The results indicated that 89.7% of all the participants had a decrease in vitamin D levels from summer to winter: 14.7% of them were vitamin D-deficient, 36.8% had insufficient vitamin D concentrations and only 48.5% where able to maintain sufficient vitamin D. The optimal cutoff point to provide assurance of sufficient serum vitamin D at the end of the winter was 40 ng/mL at the end of the summer. Sex, age and vitamin D levels at the end of the summer were significant predictors of non-sufficient vitamin D at the end of the winter. Conclusions: In this age group, a dramatic reduction in vitamin D was observed over the follow-up period. Sufficient vitamin D at the end of the summer did not guarantee vitamin D sufficiency at the end of the winter. We found 40 ng/mL as an optimal cutoff point.

Background: We identified two boys with type 3 renal tubular acidosis (RTA) and growth hormone deficiency and we sought to differentiate them from children with classic type 1 distal RTA. Methods: We reviewed all children <6 years of age with RTA referred over a 13-year period and compared the growth response to alkali therapy in these two boys and in 28 children with only type 1 distal RTA. Results: All children with type 1 RTA reached the 5th percentile or higher on CDC growth charts within 2 years of alkali therapy. Their mean height standard deviation score (SDS) improved from −1.4 to −0.6 SDS and their mean mid-parental height (MPH) SDS improved from −0.6 to 0 SDS after 2 years. In contrast, the boys with growth hormone deficiency had a height SDS of −1.4 and −2.4 SDS after 2 years of alkali and the MPH SDS were both −2.6 SDS after 2 years of alkali therapy. Growth hormone therapy accelerated their growth to normal levels and led to long-term correction of RTA. Conclusions: A child with type 1 RTA whose height response after 2 years of alkali therapy is inadequate should undergo provocative growth hormone testing.

Background: α-Klotho is a transmembrane protein that can be cleaved and act as a circulating hormone (s-klotho). s-Klotho serum levels seem to reflect growth hormone (GH) secretory status. We investigated the role of s-klotho as a reliable marker of GH secretion in short children and the factors influencing its secretion. Methods: We enrolled 40 short Egyptian children (20 GH deficiency [GHD] and 20 idiopathic short stature [ISS]). They underwent a pegvisomant-primed insulin tolerance test (ITT) and were accordingly reclassified as 16 GHD and 24 ISS. The samples obtained before and 3 days after pegvisomant administration, prior to the ITT, were used for assaying insulin-like growth factor (IGF)-I and s-klotho. Results: IGF-I and s-klotho serum levels were not significantly different (p=0.059 and p=0.212, respectively) between GHD and ISS. After pegvisomant, a significant reduction in IGF-I and s-klotho levels was found in both groups. s-Klotho significantly correlated only with IGF-I levels in both groups. Conclusions: s-Klotho mainly reflects the IGF-I status and cannot be considered a reliable biomarker for GH secretion in children.

Background: Thyroid hormones are essential for growth and brain development in childhood. Although congenital hypothyroidism (CH) is the most common reason for mental retardation, normal neurological development can be achieved through early and effective treatment. The aim of the present study was to evaluate the neurological development of CH patients aged 24–56 months. Methods: The study included a total of 116 healthy control subjects and 112 patients aged 24–56 months who were diagnosed with CH during the neonatal period and were being followed up at the Pediatric Endocrinology Department, Keçiören Training and Research Hospital, between 2012 and 2015. Demographics and clinical data of interventions and outcomes were retrieved for each patient. Statistical analysis was performed using an unpaired Student’s t-test to compare means and χ 2 -analysis to compare proportions. Results: There were no significant differences between the CH and control groups with respect to gestational age, birth weight, height standard deviation scores (HSDS) and body weight standard deviation scores (BWSDS) (p>0.05). When the groups were compared according to the Denver Developmental Screening Test (DDST), no significant differences were found in terms of personal-social, fine motor skills, or language development (p=0.325, p=0.087 and p=0.636, respectively). However, a significant difference was found between the two groups with respect to gross motor development and the result of the DDST (p=0.001). No statistical difference was found between the control and patient groups on the day of starting treatment but the number of patients with an abnormal result in the DDST starting treatment at >15 days was found to be significantly higher than the number of patients starting treatment ≤15 days. No associations were found between the DDST results of the CH group and the following factors: initial L-thyroxine (LT4) level, initial LT4 dose and the onset of treatment. Conclusions: The findings of this study indicate that the DDST results in patients with CH are generally good. Initiating treatment immediately after diagnosis and during the first days of life is absolutely imperative. However, in contrast to timing, we could not find strong evidence for determining the precise optimal dosage of LT4 to initiate treatment in children diagnosed with CH. Both the American Academy of Pediatrics and the European Society for Pediatric Endocrinology recommend 10–15 μg/kg/day as the initial dose.

Background: This study aims to analyze changes in characteristics, practice and outcomes of pediatric differentiated thyroid cancer (DTC) at our tertiary care institution. Methods: Patients <21 years of age diagnosed between 1973 and 2013 were identified. Clinicopathological data, treatment and outcomes were obtained by a retrospective review. Results: Thirteen males and 68 females were divided into Group A (n=35, diagnosed before July 1993) and Group B (n=46, diagnosed after July 1993). Group B was more likely to undergo neck ultrasound (US) (70% vs. 23%, p<0.0001) and fine-needle aspiration (FNA) biopsy (80% vs. 26%, p<0.0001). Patients in Group B more often underwent total thyroidectomy as a definitive surgical treatment (87% vs. 69%, p=0.04). There was no difference in radioactive iodine use. Recurrence-free survival was similar. Conclusions: Increased use of US and FNA has affected initial surgical management in the latter part of the study, possibly due to extension of adult DTC guidelines. The effects of the new pediatric DTC guidelines need further study.

Background: Low bone mineral density (BMD) has been frequently described in subjects with Down syndrome (DS). Reduced physical activity (PA) levels may contribute to low BMD in this population. The objective of the study was to investigate whether PA levels were related to the femoral neck bone mass distribution in a sample of 14 males and 12 females with DS aged 12–18 years. Methods: BMD was evaluated by dual energy X-ray absorptiometry (DXA) at the integral, superolateral and inferomedial femoral neck regions and PA levels were assessed by accelerometry. The BMDs between the sexes and PA groups (below and above the 50th percentile of the total PA) were compared using independent t-tests and analyses of covariance (ANCOVAs) controlling for age, height and body weight. Results: No differences were found between the BMDs of males and females in any femoral neck region (p>0.05). Females with higher PA levels demonstrated increased integral (0.774 g/cm 2 vs. 0.678 g/cm 2 ) and superolateral femoral neck BMDs (0.696 g/cm 2 vs. 0.595 g/cm 2 ) compared to those with lower PA levels (p<0.05). In males, no differences (p<0.05) were found in the BMDs between the PA groups. Conclusions: This investigation shows that females accumulating more total PA presented increased BMDs at the integral and superolateral femoral neck regions (14.1% and 17.0%, respectively) when compared to their less active peers. These data highlight the importance of PA in females with DS to counteract their low bone mass and to improve their bone health.

Background: The objectives of this study were to assess the feasibility of and compliance to collecting urine samples in pre- and postmenarcheal girls and to determine if a less than daily collection frequency was sufficient for assessing ovarian function. Methods: Twenty-five postmenarcheal girls (11–17 years) collected samples using either a two or a three samples/week protocol during one menstrual cycle. Exposure and mean estrone-1-glucuronide (E1G) and pregnanediol glucuronide concentrations were calculated, and evidence of luteal activity (ELA) was evaluated. Sixteen premenarcheal girls (8–11 years) collected one sample/month for six consecutive months. Samples were analyzed for E1G concentration. Participant compliance was calculated using dates on the urine samples and paper calendars. Results: Participants collecting three samples/week were more compliant to the protocol than those collecting two samples/week (83.6%±2.6% vs. 66.8%±6.6%; p=0.034). There were no differences (p>0.10) regarding paper calendar return (81.8%±12.2% vs. 92.9%±7.1%), recording menses (55.6%±17.6% vs. 92.3%±7.7%) or sample collection (88.9%±11.1% vs. 84.6%±10.4%) between the two protocols. The average cycle length was 30.5±1.3 days and 32% of cycles had ELA. The premenarcheal girls were 100% compliant to the protocol. Only 68.8% of participants returned the paper calendar and 81.8% of those participants recorded sample collection. The average E1G concentration was 15.9±3.8 ng/mL. Conclusions: Use of a less than daily collection frequency during one menstrual cycle in postmenarcheal, adolescent girls is feasible and provides informative data about ovarian function. Collection of one sample/month in premenarcheal girls is feasible and detects the expected low E1G concentrations. Alternate strategies to the use of a paper calendar should be considered.

Background: Maturity-onset diabetes of the young (MODY) has not been previously studied in Ukraine. We investigated the genetic etiology in a selected cohort of patients with diabetes diagnosed before 18 years of age, and in their family members. Methods: Genetic testing of the most prevalent MODY genes ( GCK , HNF1A , HNF4A , HNF1B and INS ) was undertaken for 36 families (39 affected individuals) by Sanger or targeted next generation sequencing. Results: A genetic diagnosis of MODY was made in 15/39 affected individuals from 12/36 families (33%). HNF1A and HNF4A MODY were the most common subtypes, accounting for 9/15 of MODY cases. Eight patients with HNF1A or HNF4A MODY and inadequate glycemic control were successfully transferred to sulfonylureas. Median HbA 1c decreased from 67 mmol/mol (range 58–69) to 47 mmol/mol (range 43–50) (8.3% [7.5–8.5] to 6.4% [6.1–6.7]) 3 months after transfer (p=0.006). Conclusions: Genetic testing identified pathogenic HNF1A and HNF4A variants as the most common cause of MODY in Ukraine. Transfer to sulfonylureas substantially improved the glycemic control of these patients.

Background: The purpose of this study was to evaluate the safety and convenience of initial bisphosphonate infusion therapy in inpatient and outpatient settings for patients with low bone mineral density. Methods: All data were collected from retrospective chart reviews of heterogeneous groups of patients. Abnormal findings prior to the infusion and side effects during the infusion were documented. Patients were contacted following the infusion to discuss post-infusion adverse events. Results: The majority of both outpatients (80%, n=44) and inpatients (50%, n=27) did not experience any adverse events related to the infusion. Some patients reported minor adverse events that were expected. Only one of the inpatients had a severe adverse event (SAE) after the infusion. Conclusions: For patients at low risk for severe reactions to treatment, the infusion center appears to be a safe and possibly more convenient treatment setting for both the patient and the hospital, although more expensive for the patient at our institution.

Background: Congenital hypogonadotropic hypogonadism (CHH) is classified as Kallmann syndrome (KS) with anosmia/hyposmia or normosmic (n)CHH. Here, we investigated the genetic causes and phenotype-genotype correlations in Japanese patients with CHH. Methods: We enrolled 22 Japanese patients with CHH from 21 families (18 patients with KS and 4 with nCHH) and analyzed 27 genes implicated in CHH by next-generation and Sanger sequencing. Results: We detected 12 potentially pathogenic mutations in 11 families, with three having a mutation in ANOS1 (X-linked recessive); three and four having a mutation in FGFR1 and CHD7 , respectively (autosomal dominant); and one having two TACR3 mutations (autosomal recessive). Among four patients with KS carrying a CHD7 mutation, one had perceptive deafness and two had a cleft lip/palate. Conclusions: The frequency of CHH genes in the Japanese was compatible with previous reports, except that CHD7 mutations might be more common. Furthermore, partial phenotype-genotype correlations were demonstrated in our cohort.

A 9-month-old Turkish girl was admitted several times within 3 months to the hospital in reduced general condition and with extreme tachypnea. The patient had been diagnosed with phenylketonuria (PKU) in newborn screening and has been treated with a low phenylalanine diet and amino acid supplements. Each time an unexplained pronounced metabolic acidosis was noted, and the child was treated with sodium-bicarbonate and glucose-electrolyte infusions. The acidosis with only slightly abnormal glucose, normal lactate levels and pronounced ketonuria suggested a defect in ketone body utilization. Succinyl-CoA: 3-oxoacid CoA transferase (SCOT) enzyme activity was low in patient’s fibroblasts. Mutation analysis of the corresponding OXCT1 gene revealed that the patient was a homozygous carrier of the mutation c.1523T>C (p.V508A). We conclude that SCOT deficiency should be considered in the differential diagnosis in patients with recurrent metabolic acidotic episodes, even if they are already known to have a metabolic disease unrelated to this.

Evidence suggests an increased incidence of imprinting disorders in children conceived by assisted reproductive technologies (ART). Maternal loss-of-methylation at GNAS exon A/B, observed in pseudohypoparathyroidism type 1b (PHP1B), leads to decreased expression of the stimulatory Gsα. We present a patient conceived by ART, who presented at age 4 years with delayed neurocognitive development and persistently increased creatine kinase (CK). At 6 years an elevated PTH was detected with normal calcium and a low 25(OH) vitamin D level (25OHD). Physical exam showed a narrow forehead, nasal bridge hypoplasia and micropenis. After normalizing vitamin D, PTH remained elevated and PHP1B was therefore considered as the underlying diagnosis. An almost complete loss-of-methylation was observed at GNAS exons A/B and AS, but not at exon XL, which was associated with a gain-of-methylation at exon NESP. There was no evidence of a microdeletion within the GNAS/STX16 region and analysis of several microsatellite markers for the GNAS region on Chr.20q revealed no evidence for paternal uniparental disomy (patUPD20q). Established facts Increased incidence of imprinting disorders in children conceived by assisted reproductive technologies (ART) Pseudohypoparathyroidism is caused by imprinting abnormalities. Novel Insights First report of a possible association between a methylation defects that causes PHP1B and assisted conception Increased creatine kinase level was associated with an increase in PTH concentration.

Propionic acidemia (PA) is a rare autosomal recessive metabolic disorder caused by deficiency of the mitochondrial enzyme propionyl-CoA carboxylase (PCC). This disorder mostly progresses with episodes of metabolic acidosis. Cardiomyopathy is among the cardiac complications known to occur during metabolic decompensation episodes. However, several recent papers emphasized the association of PA and long QT syndrome (LQTS) which may lead to extremely serious and fatal consequences. In this report, we describe two sisters with PA who have prolonged QT duration that were incidentally detected in an outpatient setting. LQTS was verified by electrocardiogram, stress test and 24 h rhythm holter monitoring. By this report, we want to emphasize the importance of early diagnosis of LQTS in asymptomatic patients with PA to prevent fatal complications.

Background: Proopiomelanocortin (POMC) protein, encoded by the POMC gene, is the precursor of adrenocorticotropic hormone (ACTH) that is released from the anterior pituitary gland. Homozygous mutations in the POMC gene is associated with hyperphagia, severe and early-onset obesity, adrenal insufficiency, hypopigmentation of the skin and red hair. Case presentation: A 9-year-old girl from a consanguineous family of Iraqi origin was diagnosed with type 1 diabetes. She also had a tall stature. Her laboratory assessment showed low cortisol and ACTH concentrations, normal renin and poor response to ACTH stimulation. Genetic testing revealed a novel biallelic mutation in the POMC gene. Her sibling who had severe obesity and central adrenal insufficiency was found to be a carrier of the same mutation. Both siblings had alabaster-colored skin and brown hair. Conclusions: POMC deficiency results in significant morbidity due to obesity, and it is also a potentially life threatening disease because of adrenal insufficiency. Therefore any suggestive symptom or sign of POMC deficiency warrants detailed investigations.