Band 30, Heft 4

Background: The aim of the study was to assess possible relationships between adipocyte fatty acid-binding protein (FABP4) and total body fat (TBF), abdominal fat, body fat distribution, aerobic fitness, blood pressure, cardiac dimensions and the increase in body fat over 2 years in a community sample of children. Methods: A cross-sectional study was used in a community sample of 170 (92 boys and 78 girls) children aged 8–11 years. TBF and abdominal fat (AFM) were measured by dual-energy X-ray absorptiometry (DXA). TBF was also expressed as percentage of total body mass (BF%), and body fat distribution was calculated as AFM/TBF. Maximal oxygen uptake (VO 2PEAK ) was assessed by indirect calorimetry during a maximal exercise test and scaled to body mass. Systolic and diastolic blood pressure (SBP and DBP) and pulse pressure (PP) were measured. Echocardiography was performed. Left atrial (LA) size was measured, and left ventricular mass (LVM) was calculated. A follow-up DXA scan was available in 152 children (84 boys and 68 girls). Frozen serum samples were analyzed for FABP4. Results: Partial correlations, with adjustment for sex, between FABP4 vs. ln TBF, ln BF%, ln AFM, AFM/TBF and VO 2PEAK were (r=0.69, 0.68, 0.69, 0.49 and −0.39, p<0.05 for all). Moreover, SBP, PP, LVM and LA were also weakly correlated with FABP4 (r=0.23, 0.22, 0.28 and 0.21, p<0.05 for all). Correlations between FABP4 vs. increase in TBF and AFM over 2 years were 0.29 and 0.26, p<0.05, for both. (Increase in percent body fat or change in fat distribution were not correlated.) Conclusions: Findings from this community-based cohort of young children show that increased body fat and abdominal fat, more abdominal body fat distribution, low fitness, more LVM and increased LA, increased SBP and PP were all associated with increased levels of FABP4. Increase in TBF and abdominal fat over 2 years were also associated with increased levels of FABP4.

Background: Previous studies suggest that vitamin D may play a role in cardiovascular and metabolic health. Oxidative stress has also been implicated in the development of cardiovascular disease. Evidence suggests that vitamin D deficiency may contribute to the occurrence of oxidative stress. This study aimed to determine whether treatment and correction of vitamin D deficiency in obese children led to changes in their metabolic profile, independent of changes in adiposity. In addition, we aimed to determine whether vitamin D deficiency and oxidative stress are causally related in obese children. Methods: In the retrospective arm, chart review identified 32 obese children who experienced normalization of vitamin D deficiency or insufficiency with vitamin D supplementation. We then correlated laboratory and anthropometric data with vitamin D levels. In the prospective arm of the study, urinary 8-isoprostane and hydrogen peroxide were measured before and after correction of vitamin D deficiency/insufficiency and correlated to vitamin D levels in seven patients. Results: In our predominantly Hispanic population of obese children in an urban setting, we demonstrated a cause-effect relationship between vitamin D deficiency and oxidative stress. In contrast, we found no association between vitamin D status, adiposity, and markers of insulin sensitivity, nor any effect of vitamin D treatment on the same parameters. Conclusions: These discordant findings suggest a differential effect of vitamin D on cardiovascular risk factors such as oxidative stress and insulin resistance. To confirm these findings, further prospective studies with larger sample size and longer follow-up are warranted.

Background: The association of low serum 25 hydroxy cholecalciferol (25OHD) levels with high glucose level and diminished insulin sensitivity suggests that vitamin D (VD) may modulate insulin metabolism. The aim of the study was to screen for vitamin D deficiency (VDD) in pediatric patients with type 1 diabetes (T1D) and study the effect of VD supplementation on their glycemic control and insulin requirements. Methods: A prospective cohort study including 50 patients with T1D. VD level was assessed initially and after 3 months of VD supplementation (in those with VDD). HbA 1c and insulin requirements were studied at 0, 3 and 6 months of supplementation. Results: Fifty patients with T1D were included with mean diabetes duration of 4.11±2.34 years. VD level ranged from 0.2 to 33 ng/mL. VD status correlated significantly with daily insulin dose (p=0.030, r=0.306) and HbA 1c (p<0.001, r=0.243). Thirty-five patients (70%) had VDD and were allocated for VD supplementation for 3 months. The mean HbA 1c improved significantly after supplementation (p=0.003), followed by a significant deterioration at 6 months with no change in their insulin requirements at 3 or 6 months. Conclusions: VD was highly prevalent in Egyptian T1D patients. VD supplementation improved glycemic control at 3 months after therapy with no reduction in insulin requirements.

Background: Universal vitamin D supplementation is controversial. Preventative examinations and public health initiatives in former East Germany that included vitamin D prophylaxis for children were regulated by official recommendations and guidelines. The aim of this study is to analyse the impact of a standardised nationwide guideline for universal supplementation with 400 International Units (IU) vitamin D3/day during the first year of life on clinical and biochemical parameters and the influence of surrounding factors. Methods: This is a cross-sectional analysis looking at data from a field study of 3481 term-born children during their first year of life that was conducted in 1989. Results: There were no significant clinical signs of rickets. 25 hydroxyvitamin D (25(OH)D) (mean and SEM, total analyses n=572) after birth (n=28) was 36(7) nmol/L, at 1 month 64(4) nmol/L (n=70, p<0.0001), 91(5) nmol/L at 3 months (n=95, p<0.0001), 65(8) nmol/L at 8 months (n=21, p=0.005) and ranged between 33 and 109 nmol/L until 12 months. Less than 0.2% of analyses revealed pathological levels for calcium or phosphate. Alkaline phosphatase (ALP) levels (n=690) were >1500 U/L (95th percentile) in 3.6%. Participants were on breastmilk or vitamin D-free formula, with solids added from 6 months of age. There were seasonal variations in 25(OH)D levels with a rise during spring and autumn. Thus this analysis is unique as sun exposure and supplementation can be considered as the only vitamin D sources. Conclusions: We conclude that universal supplementation with 400 IU of vitamin D3 during the first year of life is safe and provides sufficient 25(OH)D levels in Germany.

Background: Congenital hypothyroidism (CH) is a common and preventable cause of intellectual disability for which early diagnosis is difficult without newborn screening. Genetic and environmental factors, race, ethnicity, sex, and pregnancy outcomes were noted as risk factors. In the study we aimed to determine the incidence of CH among different ethnic groups in the capital of Macedoina – a multiethnic city. Methods: A 14-year retrospective cohort analysis was performed on 121,507 newborns in the capital of Macedonia, Skopje, screened for whole-blood thyroid-stimulating hormone (TSH), in dry blood spots collected 48–72 h after birth, during the period 2002–2015. A TSH value of 15 mIU/L was used as cutoff point until 2010 and 10 mIU/L thereafter. Results: Primary CH was detected in 46 newborns (female to male ratio 1.3) with overall incidence of 3.8/10,000 (1/2641). The incidence of primary CH was significantly increased after lowering the TSH cutoff value (p=0.038), primarily due to detected neonates with transient CH for this period. Ethnic differences in the incidence of primary CH were detected. CH incidence among Roma neonates (6.7/10,000) was significantly higher (p<0.05) than the incidence detected in Macedonians (3.9/10,000) or Albanians (3.7/10,000). Conclusions: Increased incidence of CH in Roma newborns was detected as compared to other ethnicities in the capital of Macedonia. Further analysis of factors in direct interrelationship with the increased CH incidence in Roma newborns, as well as elucidation of impact of the CH incidence in this ethnicity on the overall incidence in Skopje, is warranted.

Background: Ketogenic diet (KD), which is high in fat and low in carbohydrates, mimics the metabolic state of starvation and is used therapeutically for pharmacoresistant epilepsy. It is known that generation of triiodothyronine (T3) from thyroxine (T4) decreases during fasting periods. The aim of this study was to evaluate the thyroid function of children receiving KD for at least 1 year due to drug-resistant epilepsy. Methods: A total of 120 patients [63 males, 52.5%; mean age 7.3±4.3 years, median interquartile range (IQR): 7.0 (4–10 years)] treated with KD for at least 1 year were enrolled. Seizure control, side effects, and compliance with the diet were recorded, and free T3, free T4, and thyroid-stimulating hormone (TSH) levels were measured at baseline and at post-treatment months 1, 3, 6, and 12. The Mann-Whitney U-test, repeated measures analysis of variance (ANOVA) with post-hoc Bonferroni correction, and logistic regression analysis were used for data analysis. Results: Hypothyroidism was diagnosed and L-thyroxine medication was initiated for eight, seven and five patients (20 patients in total, 16.7%) at 1, 3, and 6 months of KD therapy, respectively. Logistic regression analysis showed that baseline TSH elevation [odds ratio (OR): 26.91, 95% confidence interval (CI) 6.48–111.76, p<0.001] and female gender (OR: 3.69, 95% CI 1.05–12.97, p=0.042) were independent risk factors for development of hypothyroidism during KD treatment in epileptic children. Conclusions: KD causes thyroid malfunction and L-thyroxine treatment may be required. This is the first report documenting the effect of KD treatment on thyroid function. Thyroid function should be monitored regularly in epileptic patients treated with KD.

Background: Insulin resistance (IR) in adults has been associated with intrauterine growth restriction (IUGR). Leptin and adiponectin correlations with anthropometric parameters and IR at 72 h in discordant twins were tested. Methods: We included 24 discordant (birth weight discordance ≥20% in relation to the heavier cotwin) and 30 concordant (birth weight discordance ≤10%) twins. Results: A correlation between leptin (but not adiponectin) level and birth weight (BW), birth length and head circumference in IUGR twins was recorded (p<0.05). Insulin sensitivity (IS) and homeostatic model assessment (HOMA)-IR in IUGR twins were similar to appropriate-for-gestational-age cotwins and unrelated to adipokines. In IUGR twins, adiponectin and insulin associated positively. In larger concordant twins’ leptin level correlated with HOMA-IR and insulin. Conclusions: Leptin, but not adiponectin, levels correlate positively with anthropometric parameters in IUGR twins. IR in IUGR twins is unrelated to adipokines in the first few days of life.

Abstract: Background: The majority of children who present for evaluation of tall stature fall under the diagnosis of constitutional tall stature (CTS). Methods: To investigate mechanisms of tall stature, we evaluated serum IGF-I values and the expression of the GHR gene in the peripheral blood cells of 46 subjects with normal height, 38 with tall stature and 30 healthy children with short stature. Results: Our results showed significantly lower IGF-I levels in children with short stature (−0.57±0.18 SDS) compared to control children (0.056±0.19 SDS; p<0.0001) and to subjects with tall stature (0.594±0.17; p=0.00067). Furthermore, we found significantly higher GHR gene expression levels in tall children (321.84±90.04 agGHR/5×10 5 agGAPDH) compared with other groups of subjects (short children: 30.13±7.5 agGHR/5×10 5 agGAPDH, p<0.0001; controls: 86.81ag±19.5 GHR/5×10 5 agGAPDH, p=0.035). The GHR gene expression level in short children was significantly lower compared with control subjects (p=0.0068). Conclusions: Significantly higher GHR gene expression levels in tall subjects suggests a sensitization of the GHR-IGF system leading to overgrowth in CTS.

Background: The clinical significance of pericentric inversion of chromosome 9 [inv (9)] remains unclear. Methods: This case control study assessed girls with short stature. According to karyotypes, the subjects were divided into inv (9) [46,XX,inv (9)(p12q13) and 46,XX,inv (9)(p11q13)], Turner syndrome (45, X) and control (normal 46, XX) groups, respectively. Detailed clinical features were compared. Results: Height standard deviation score (SDS) values at diagnosis were −2.51±0.58, −3.71±2.12 and −2.5±1.24 for inv (9), (45, X) and control groups, respectively (p=0.022). The inv (9) group showed lower body mass index (BMI) values compared with the (45, X) and control groups (F=5.097, p=0.008). Similar growth hormone deficiency (GHD) incidences were found in all groups. Interestingly, height SDS was positively correlated with mother height and patient BMI SDS (r=0.51, p=0.036; r=0.576, p=0.023, respectively) in the inv (9) group. In the (45, X) group, height SDS was positively correlated with birth weight (r=0.392, p=0.039). Conclusions: Short stature in inv (9) girls was correlated with low birth weight (LBW) and mother height.

Abstract: Background: Hereditary vitamin D-resistant rickets (HVDRR) is an autosomal recessive disorder caused by mutations in the vitamin D receptor ( VDR ) gene. Variable phenotypes have been associated with these mutations, and some of these were linked to the effects they have on the interacting partners of VDR, mainly the retinoic X receptor (RXR). Methods: We examined four patients with HVDRR from three unrelated Lebanese families. All parents were consanguineous with normal phenotype. We used Sanger sequencing to identify mutations in the coding exons of VDR . Results: Two homozygous mutations (p.R391S and p.H397P), both in exon 9 of the VDR gene, were identified. Phenotype/genotype association was not possible even for the same mutation. Alopecia was seen only with the p.R391S mutation. Despite a comparable rachitic bone disease, the patients showed different responsiveness to large doses of alfacalcidol (1-α-hydroxy vitamin D3) supplementation. Conclusions: This is the first report of VDR mutations in Lebanon with promising clinical outcomes despite the severity of the phenotypes.

Background: Excess weight, unhealthy lifestyle habits and their sequelae have become a well-recognized public health problem in most countries. The objective of the study was to examine the relationship of adolescent overweight/obesity with behavioral habits and their association with blood pressure (BP) and lipid profile. Methods: Anthropometric parameters, lifestyle, BP and lipid profile of 736 adolescents were evaluated cross-sectionally. The classifications of normal weight, overweight and obese were based on BMI z-scores. Results: About 42.1% of adolescents were overweight/obese, 11.3% were smokers, 33.2% consumed alcohol and 34% reported low activity. Males began smoking earlier, consumed alcohol more often, exercised less and spent more screen time than females. Alcohol consumption was more prevalent among smokers and was associated with higher BP and dyslipidemia. Smokers exercised less intensely and had lower high density lipoprotein-cholesterol (HDL-C) than non-smokers. Obesity was a risk factor for higher BP and dyslipidemia. Longer screen time was associated with higher triglycerides, while intense physical activity with lower systolic BP. Conclusions: Obesity is related to an adverse lipid and BP profile during adolescence. Clustering of hazardous habits was observed, which is known to aggravate the cardiovascular risk.

Abstract: To elucidate the effect of early growth patterns on the metabolic sensitivity to adiposity, we examined the relationship between the homeostatic model assessment of insulin resistance (HOMA-IR) and body mass index (BMI) levels at 12 years of age in 101 boys and 91 girls in a birth cohort. Children with an increase in BMI from the ages of 1.5 to 3 years exhibited a greater increase of HOMA-IR per BMI increase at 12 years of age compared to those with a decrease in BMI or stable BMI from 1.5 to 3 years. This suggests that children who show an increase in BMI from 1.5 to 3 years, a period normally characterized by a decreased or stable BMI, are more prone to developing insulin resistance at 12 years of age.

Background: Glycogen synthase deficiency, also known as glycogenosis (GSD) type 0 is an inborn error of glycogen metabolism caused by mutations in the GYS2 gene, which is transmitted in an autosomal recessive trait. It is a rare form of hepatic glycogen storage disease with less than 30 cases reported in the literature so far. The disorder is characterized by fasting hyperketotic hypoglycemia without hyperalaninemia or hyperlactacidemia. It is a glycogenosis with lack of liver glycogen synthesis, therefore hepatomegaly is not observed in patients with glycogen synthase deficiency. Symptoms of fasting hypoglycemia in patients with glycogen storage disease type 0 (GSD0) usually appear for the first time in late infancy when weaning from overnight feeds. Seizures associated with low blood glucose may also occur, but they are rare. Clinical management is therefore based on frequent meals composed of high protein intake during the day and addition of uncooked cornstarch in the evening. Case presentation: Herein we report three new cases of liver glycogen synthase deficiency (GSD0). The first patient presented at the 4 years of age with recurrent hypoglycemic seizures. The second patient who is the brother of the first patient presented at 15 months with asymptomatic incidental hypoglycemia. Glucose monitoring in both patients revealed daily fluctuations from fasting hypoglycemia to postprandial hyperglycemia and lactic acidemia. A third patient was consulted for ketotic hypoglycemia and postprandial hyperglycemia at the 5 years of age. Conclusions: Genetic analyses of the siblings revealed homozygosity for mutation c.736C>T on the GYS2 gene confirming the diagnosis. The third patient was found to be homozygous for c.1145G>A. GSD0 is more common than previously assumed. Recognition of the variable phenotypic spectrum of GSD0 and routine analysis of GYS2 are essential for the correct diagnosis.

Background: Mucopolysaccharidosis IIIB (MPS IIIB) is a genetic disease characterized by mutations in the NAGLU gene, deficiency of α-N-acetylglucosaminidase, multiple congenital malformations and an increased susceptibility to malignancy. Because of the slow progressive nature of this disease and its atypical symptoms, the misdiagnosis of MPS IIIB is not rare in clinical practice. This misdiagnosis could be avoided by using next-generation sequencing (NGS) techniques, which have been shown to have superior performance for detecting mutations underlying rare inherited disorders in previous studies. Case presentation: Whole exome sequencing (WES) was conducted and the putative pathogenic variants were validated by Sanger sequencing. The activity of MPS IIIB related enzyme in the patient’s blood serum was assayed. A heterozygous, non-synonymous mutation (c.1562C>T, p.P521L) as well as a novel mutation (c.1705C>A, p.Q569K) were found in the NAGLU gene of the patient. The two mutations were validated by Sanger sequencing. Our data showed that this patient’s c.1562C>T, p.P521L mutation in the NAGLU gene was inherited from his father and c.1705C>A, p.Q569K was from his mother. The diagnosis was further confirmed by an enzymatic activity assay after patient recall and follow-up. Conclusions: Our results describe an atypical form of MPS IIIB and illustrate the diagnostic potential of targeted WES in Mendelian disease with unknown etiology. WES could become a powerful tool for molecular diagnosis of MPS IIIB in clinical setting.

Background: Congenital hyperinsulinism (CHI) can present with considerable clinical heterogeneity which may be due to differences in the underlying genetic etiology. We present two siblings with hyperinsulinaemic hypoglycaemia (HH) and marked clinical heterogeneity caused by compound heterozygosity for the same two novel ABCC8 mutations. Case presentation: The index patient is a 3-year-old boy with hypoglycaemic episodes presenting on the first day of life. HH was diagnosed and treatment with intravenous glucose and diazoxide was initiated. Currently he has normal physical and neurological development, with occasional hypoglycaemic episodes detected following continuous fasting on treatment with diazoxide. The first-born 8-year-old sibling experienced severe postnatal hypoglycaemia, generalised seizures and severe brain damage despite diazoxide treatment. The latter was stopped at 6-months of age with no further registered hypoglycaemia. Genetic testing showed that both children were compound heterozygotes for two novel ABCC8 missense mutations p.I60N (c.179T>A) and p.G1555V (c.4664G>T). Conclusions: These ABCC8 missense mutations warrant further studies mainly because of the variable clinical presentation and treatment response.

Background: Adenocorticotropic hormone (ACTH)-dependent Cushing’s syndrome in infancy is extremely rare. We describe the case of a sacro-coccygeal ectopic ACTH-secreting immature teratoma in an infant who also presented the triad of defects characteristic of Currarino syndrome. Case presentation: A girl was born with a large immature teratoma in the sacro-coccygeal region associated with anal atresia. At the age of 7 days, the concentration of α-fetoprotein (AFP) was above the age-specific normal range. Two non-radical surgical excisions of the tumour were performed. At the age of 7 months, she developed polyphagia, acne, hirsutism, hypertension and hypokalemia with elevated ACTH and absence of serum cortisol circadian rhythm. Immunostaining of tumour tissue showed ACTH-immunoreactive cells. Due to unsuccessful therapy with ketoconazole and resistance to antihypertensive medications [blood pressure (BP) 210/160 mmHg], metyrapone was administered, which controlled her ACTH and cortisol levels in the normal range. Following further removal of tumour bulk after three operations during the first year of life, there was a decrease of BP to normal values. Conclusions: A rare case of ectopic ACTH syndrome causing Cushing’s syndrome in infancy in the context of Currarino syndrome is reported. Radical surgery has resulted in excision of the tumour and current control of Cushing’s syndrome.