Band 33, Heft 3

Background The prevalence of both vitamin D (VitD) deficiency and type 1 diabetes mellitus (T1DM) has increased worldwide over the last few decades. The objectives of this study were: (1) to evaluate the prevalence of VitD deficiency and insufficiency among Israeli youth with T1DM and (2) to assess the association between VitD status, seasonality and T1D glycemic control characteristics. Methods This was a multi-centered, cross-sectional study. VitD levels were routinely tested during the years 2008–2011 in T1DM patients aged up to 21 years. Medical records were reviewed for demographic, clinical and laboratory characteristics. Results The study population consisted of 199 participants (53% males), mean age 12.24±4.11 years, mean T1DM duration 3.77±3.43 years. VitD levels were within the normal range in 19.6%, insufficient (15–29 ng/mL, 37–72 nmol/L) in 62.3% and deficient (<15 ng/mL, <37 nmol/L) in 18.1%. Mean VitD level was higher during the summer than during spring, autumn and winter (28.65 ng/mL, 23.16 ng/mL, 21.65 ng/mL, 17.55 ng/mL, respectively, p<0.001). Mean VitD level was higher among secular patients compared to the religious (whole-year heavily dressed) population (23.57 ng/mL, 15.54 ng/mL, respectively, p<0.001). VitD level was negatively associated with body mass index calculation of standard deviation scores (BMI-SDS), high-density lipoprotein (HDL) and age at diagnosis (r=−0.171, p=0.016; r=−0.149, p=0.043; r=−0.150, p=0.037, respectively). No association was demonstrated with disease duration and glycemic control indices and metabolic parameters. Conclusions VitD insufficiency is largely prevalent among Israeli youth with T1DM, as is in Israeli youth in general. The VitD level is associated with seasonality, clothing habits and BMI.

Background Hypothalamic damage may alter glucagon-like peptide-1 (GLP-1) secretion and be involved in the pathogenesis of obesity. We aim to evaluate the metabolic features and the dynamic changes of GLP-1 levels during an oral glucose tolerance test (OGTT) in children with hypothalamic obesity (HO) compared with simple obesity controls. Methods Subjects included eight patients (six females, aged 9–16 years) with hypothalamo-pituitary tumors who later developed obesity and eight controls with simple obesity matched for age, body mass index (BMI), gender and puberty. We assessed the metabolic syndrome features, fat mass, severity of hyperphagia using a standardized questionnaire, and measured glucose, insulin and GLP-1 levels during a standard 75 g OGTT. Results Age, gender distribution, pubertal status and BMI-Z scores were not significantly different. Subjects with HO had higher fasting triglycerides (TG) than controls (128 vs. 94 mg/dL; p=0.05). Four HO subjects and three controls met the criteria for the metabolic syndrome. Fasting and 120 min post-glucose load GLP-1 levels were significantly higher in HO patients than in controls (21.9 vs. 19.7 pg/mL; p=0.025, 22.1 vs. 17.7 pg/mL; p=0.012). Patients with HO had significantly higher hyperphagia scores than in simple obese controls (13 vs. 2.5; p=0.012). Conclusions Patients with HO appear to have more metabolic complications and hyperphagia than controls with simple obesity. Impaired satiety may play an important role in HO. Fasting and glucose-induced serum GLP-1 concentrations seem to be altered in HO patients and could be a part of the pathogenesis of HO.

Background The intima-media thickness of the carotid artery (cIMT) and endothelial dysfunction are associated with cardiovascular (CV) disease. Objectives To evaluate the correlation between cIMT, brachial intraluminal diameter and flow-mediated vasodilation on the reactive hyperemia phase in adolescents with obesity with predictors of CV risk. Methods Seventy-three pubertal patients with overweight or obesity were evaluated (45 girls) with a mean (standard deviation [SD]) age of 12.9 (2.5) years. Patients underwent anthropometric measurements and had the lipid profile, oral glucose tolerance test (oGTT) and serum intercellular adhesion molecule-1 (sICAM-1) levels analyzed. The ratios of the waist circumference (WC)/height (WHtR) and triglycerides (TG)/high-density lipoprotein cholesterol (HDL-C), homeostatic model assessment of insulin resistance (HOMA-IR), the Matsuda index and insulin area under the curve (AUC) were calculated. All patients were evaluated for cIMT and arterial blood flow velocity of the brachial artery. Results 75.3% of the patients had high cIMT values. We found a positive correlation between WHtR and cIMT (r = 0.233; p = 0.050). There was a positive correlation between sICAM-1 and insulin AUC (r = 0.323; p = 0.012) and WHtR (r = 0.258; p = 0.047). Patients with abnormal arterial dilation had higher sICAM-1 values (p = 0.02) despite having smaller WHtR (p = 0.046). Conclusions These adolescents with obesity had high cIMT values. Insulin resistance was associated with sICAM-1. Endothelial dysfunction was positively correlated with sICAM-1. There is no consensus about what the best laboratorial approach to evaluate insulin resistance in adolescents is, and the cutoff values of each method are arbitrary. So, as we saw earlier, the association between anthropometric data (WHtR) and ultrasound findings could be useful to evaluate the CV risk of these adolescents with obesity, because of its practical, direct and low-cost value.

Introduction Hyperandrogenism (HA), either clinical or biochemical, is associated with obesity in adolescent girls. Long chain polyunsaturated fatty acids ω3 (LCPUFA-ω3) play protective roles in some obesity-associated morbidities, but their contribution to preventing HA is unclear. Our aim was to examine the potential positive relationships between erythrocyte LCPUFA-ω3, with or without supplementation, and hyperandrogenemia. Methods Secondary analysis of a clinical trial that was conducted previously to analyze the effect of LCPUFA-ω3 on insulin resistance and body weight. Here, we present a cross-sectional analysis of 180 girls with obesity, and a longitudinal analysis of 117 girls who completed a 3-month supplementation period (57 LCPUFA-ω3 [DO3] and 60 placebo [DP)]). Dehydroepiandrosterone sulfate (DHEAS), total testosterone (TT) and steroid hormone binding globulin (SHBG) were measured with chemiluminescence; free testosterone (FT) was calculated. Erythrocyte fatty acids were determined by gas chromatography. Non-parametric statistics was used for analysis. Results In cross-sectional analysis, age (odds ratio [OR] = 1.35; 95% confidence interval [CI] = 1.03, 1.78; p = 0.027), insulin (OR = 1.05; 95% CI: 1.00, 1.10; p = 0.018), and erythrocytes eicosapentaenoic acid (EPA) (OR = 0.04; 95% CI: 0.01, 0.65; p = 0.012) were predictors of hyperandrogenemia (FT >0.63 ng/mL). In longitudinal analysis, EPA, adiponectin and SHBG increased, while FT decreased, in the DO3 group (p < 0.05). The risk of hyperandrogenemia at the end of follow-up was predicted by basal hyperandrogenemia (OR = 18.16, 95% CI: 5.37, 61.4; p < 0.001) and by increases in EPA (OR = 0.40; 95% CI: 0.01, 0.65; p = 0.06 marginal significance). Conclusions Our results suggest a preventive role of EPA on the risk for hyperandrogenemia in girls with obesity, but further studies are needed to demonstrate a benefit.

Background Phenylketonuria (PKU) is a common metabolic disorder with great burden if left untreated or undiagnosed. Genetic variations in the phenylalanine hydroxylase ( PAH ) gene may be widely varied across different regions of a country. By knowing the most common mutations, diagnostic work-ups will be offered sooner and with lower costs for patients. The present study defines the most common genetic variations in the PAH gene in Khorasan province of Iran. Methods The present cross-sectional study took place in Khorasan province of Iran within a 6-year period starting from 2012 to 2018. Every patient who had been referred as suspicious PKU cases or referred for prenatal diagnosis was included in the present study. Results A total number of 122 individuals with a mean age of 26.22 years were enrolled in the present study. The most frequent genetic variations in the PAH gene were c.1066-11G > A and c.143 T > C. Exon 7 carried the most genetic variations compared to any single exon. Also, three patients had compound heterozygous status for c.727 C > T/c.1066-11 G > A in exon 7 and 11 of the PAH gene. Conclusions Mutations in the PAH gene are widely varied among different populations, and our results confirmed this fact. Determination of the most prevalent mutations and polymorphisms in each region will reduce the time and cost of diagnosing such preventable diseases and will therefore reduce the disease burden.

Background Diet plays an integral role in the maintenance of oral health, but dietary modifications due to medical problems such as phenylketonuria (PKU) can have adverse effects on oral health. This descriptive study was performed to evaluate the oral health status of children with PKU. Methods One hundred and ninety-seven patients with PKU aged between 1 and 22 years were evaluated. Clinical evaluations were performed by one experienced dentist regarding dental caries, gingival health and dental erosion. Categorical variables were assessed with descriptive statistics. Differences in feeding frequencies and sociodemographic characteristics were compared regarding dental caries using chi-square (χ 2 ) tests. Results One hundred and thirty-two patients (67%) had dental caries. The mean plaque index (PI) and gingival index (GI) values were 1.37 ± 0.58 and 1.40 ± 0.64, respectively, which shows moderate plaque accumulation and moderate gingival inflammation. Of the patients, 85.3% did not brush their teeth regularly and 90.4% had never visited a dentist before. No statistically significant differences were found in dental caries according to feeding frequencies (p = 0.448). Conclusions Despite the high prevalence of caries in patients with PKU, most had never seen a dentist. Physicians must encourage patients with PKU and their parents to have regular dental visits to maintain an optimal general and oral health.

Background The amino acids glutamine plus glutamate, phenylalanine and tyrosine are implicated in neurotransmission. We aimed to evaluate these amino acid blood concentrations in full-term breastfed infants with different birth weight (BW) perinatally. Methods Breastfed full-term infants (n = 6000, males 3000, females 3000) BW 2000–4000 g were divided into four equal groups. Both males and females Groups A, 2000–2500 g, B 2500–3000 g, C 3000–3500 g, D 3500–4000 g. Blood samples on Guthrie cards, were taken on the 3rd day of life and quantified via a liquid chromatography tandem mass spectrometry (LC-MS/MS) method. Results Glutamine plus glutamate mean values were found to be statistically significantly different between males vs. females in all the studied groups. The highest values were determined in both males and females in group D. Statistically significantly higher values of phenylalanine appeared in group D vs. other groups. Tyrosine mean values were calculated to be statistically significantly different in both sexes in group A compared to other groups. Conclusions Differences of glutamine plus glutamate, phenylalanine and tyrosine levels among full-term newborns with different BW are presented for the first time in the literature. Newborns with BW 3000–4000 g are benefited by having higher concentrations of the mentioned neurotransmission related amino acids. Neonatal screening reference values for these amino acids in relation to BW could be established, not only for preterm and low BW infants but also for full-term newborns with BW >3000 g.

Background To determine the incidence of congenital hypothyroidism (CH) with a delayed increase in thyroid-stimulating hormone (TSH) levels in preterm infants and to describe the associated factors. Methods A prospective newborn screening (NBS) was conducted in 122 very low birth weight (VLBW) premature neonates born between June 2016 and September 2017. A dried blood spot thyroid stimulating hormone (TSH) level ≥15 mIU/L at 7 and 15 days of life, ≥10 in serum at the second screen or ≥5 at the third screen was defined as positive for CH. A concomitant increase in the TSH level and normal free thyroxine (T4) level was classified as hyperthyrotropinemia (HT). Results Before the first month of life, no cases of CH were identified. However, the second and third NBS identified 10 and six subjects with HT, respectively, but no cases of CH. The overall cumulative incidence of HT was 1:8. Small for gestational age (SGA) was a variable that was significantly associated with HT, even after the exclusion of patients with Down syndrome. Conclusions A high incidence of HT, but not CH, was found after the first month of life in preterm infants. Being SGA was strongly associated with having higher TSH. The need for repeating TSH screening after the first month of life in this population remains to be established.

Introduction Only about 30% of pediatric patients with Graves’ hyperthyroidism achieve remission with medical therapy, and therefore radioactive iodine (RAI) therapy is often used as a definitive treatment. Although the goal of RAI is permanent hypothyroidism, this is not consistently achieved. We conducted a chart review to determine the factors associated with the success of RAI. We also tried to determine optimal follow-up post RAI and if there was an optimal L-thyroxine dose that would normalize the hypothyroid state quickly. Methods This is a retrospective chart review of Graves’ patients who underwent RAI between 2008 and 2017. We included age, sex, time from diagnosis, thyroid gland size, total dose of I-131 and dose in μCi/g of thyroid tissue. Patients were grouped based on outcome and analyzed using univariate and multivariate logistic regression. Follow-up thyroid levels post RAI and after starting l-thyroxine were analyzed. Results There were 78 ablations including six repeat ablations. Seventy-three percent became hypothyroid, 23% remained overtly or subclinically hyperthyroid, and 4% were euthyroid. Smaller thyroid size (36.5 vs. 47.4 g; p = 0.037) and higher dose of I-131 (242 vs. 212 μCi/g thyroid tissue; p = 0.013) were associated with a higher likelihood of hypothyroidism. Most patients remained hyperthyroid at 1 month post RAI, but by 3 months the majority became hypothyroid. There was no clear L-thyroxine dose that normalized hypothyroidism quickly. Conclusions An I-131 dose close to 250 μCi/g of thyroid tissue has a higher likelihood of achieving hypothyroidism. Testing at 2–3 months after RAI is most helpful to confirm response to RAI.

Background Recently, urinary excretion of the tetrasaccharide 6-α-D-glucopyranosyl-maltotriose (Glc4) has been proposed as a marker for the diagnosis and monitoring of Pompe disease (PD). We aimed to determine the reference intervals and reliable decision-making levels of urine tetrasaccharide concentrations for the diagnosis of infantile- and late-onset Pompe patients in the Turkish population. Methods In this study, nine patients with PD (five of them with late-onset PD [LOPD]) and 226 healthy individuals (aged 0–64 years) were included. Urine Glc4 concentrations were determined using the ultra-high-performance liquid chromatography (UHPLC) tandem mass spectrometry (MS/MS) method. Results Our data showed that the urine tetrasaccharide levels decreased with age in healthy individuals (p < 0.001, r = −0.256). It was higher especially during the first year of life compared to that in the elder subjects. The tetrasaccharide level of Pompe patients was higher compared to that of healthy controls of the same age: 99 ± 68 mmol/mol creatinine for infantile onset vs. 4.0 ± 3.0 mmol/mol creatinine for healthy controls of the same age group and 12.1 ± 17.4 mmol/mol creatinine for late onset vs. 1.7±1.2 mmol/mol creatinine for healthy controls of the same age group. Conclusions The results of this study showed that the reference intervals of tetrasaccharide in urine changed over time; therefore, it is critically important to define age-based decision levels for the diagnosis of LOPD.

Background This study aimed to investigate the presence of sleep disturbances in children with Prader-Willi syndrome (PWS) using the Sleep Disturbance Scale for Children (SDSC). Methods The SDSC, which was designed to identify the presence and severity of different sleep disorders, was applied to 50 patients with PWS and 112 controls. Results Patients with PWS achieved worse scores in the sleep-disordered breathing and disorders in initiating and maintaining sleep in the SDSC questionnaire as compared with controls. We also observed that patients with PWS were more prone to having hyperhidrosis. We did not observe significant differences in the presence of other types of sleep disorders (such as hypersomnolence) between the PWS and control groups. Conclusions The results obtained with the SDSC questionnaire showed that children with PWS have more sleep breathing disorders and disorders in initiating and maintaining sleep as compared to controls. Additionally, we demonstrated that patients with PWS associates significantly with the presence of hyperhidrosis during sleep. However, SDSC was not reliable to identify the excessive daytime somnolence in patients with PWS, as previously reported in the literature.

Background Juvenile breast hypertrophy is characterised by massive enlargement of the breast in the peri-pubertal period. We aimed to analyse body size measurements (body mass index [BMI], waist-to-hip circumference ratio [WHR]), digit ratio (ratio of II and IV digits’ length [2D:4D]) and oestrogen receptor (ER) alpha (ERα) and progesterone receptors (PRs) in the breast gland in women with juvenile gigantomastia. Methods The study involved 30 women (mean age 25.7 years) (mean age of onset – 14.8 years). ERα and PR expressions were detected immunohistochemically in breast gland samples. For comparison, 100 controls (50 women and 50 men) were included. Results BMI and WHR in women with gigantomastia were higher than in control women and the former had a higher WHR than expected for their BMI. 2D:4D in the examined women did not differ from that in control women. However, left 2D:4D was negatively related to the age of gigantomastia onset. There were no correlations between ER and PR expressions and the analysed body and digit ratios. Conclusions The lack of a relationship between 2D:4D and juvenile breast hypertrophy may suggest that foetal exposure to sex hormones may not be crucial in its aetiology. However, the link between high left 2D:4D and early development of gigantomastia suggests that prenatal sex hormones have a role in its development timing. High WHR, and particularly high WHR relative to BMI, may indicate that these women had at some stage of development higher circulating androgens, which may have been converted to oestrogens in breasts due to local aromatase activity. Verification of this hypothesis could allow consideration of the role of aromatase inhibitors in juvenile breast hypertrophy.

Objectives We aimed to assess whether age at menarche and pubertal development (Tanner stage) are related to gluten-free diet (GFD) adherence, hormonal status, micro-nutrient levels and body mass index (BMI) in children with celiac disease (CD). Methods In this two-center, cross-sectional study, CD patients and healthy individuals were studied. CD patients were re-evaluated after 1 year of follow-up. Height, weight, Tanner stage, age at menarche and diet compliance were recorded. Blood samples for anti-tissue transglutaminase IgA (TTG), pituitary gonadotropins, gonadal hormones, prolactin and micronutrients (folate, vitamin B12, vitamin D, ferritin, iron and, iron-binding capacity [IBC]) were assayed. Results Consecutive age- and sex-matched 228 celiac patients (12.92 ± 2.35 years; 67.9% female) and 135 non-celiac healthy individuals (12.77 ± 2.25 years; 65.2% female) were studied. Tanner stage was significantly higher in the control group for both girls and boys (p < 0.05). The mean age at menarche was significantly lower in healthy individuals (13.13 ± 1.01 vs. 12.15 ± 0.97, p < 0.001). By multivariate analysis, GFD adherence, transferrin saturation (sTrf), total IBC (TIBC) and vitamin D status were found to be positively correlated with Tanner stage (p < 0.05). After 1 year, 192 of the CD patients were re-evaluated. GFD compliance was better (TTG levels: 135.59 ± 73.88 vs. 71.53 ± 69.40, p < 0.001) and it was correlated with Tanner stage (r = 0.49, p < 0.01), sTrf (r = 0.66, p < 0.01) and IBC (r = 0.23, p < 0.05). Conclusions Our data show that adequate weight gain, adherence to GFD, sufficient iron and vitamin D status are essential factors for salubrious puberty in CD patients.

Introduction According to the current classification of the Lawson Wilkins Pediatric Endocrine Society (LWPES) and the European Society for Pediatric Endocrinology (ESPE) of Disorders of Sex Development (DSD), etiologies vary around the world. Ethnic or genetic diversity probably explains this variability. We therefore conducted the present study on etiologies of DSDs in a country from central Africa. Methods We carried out an observational retrospective study at the Pediatric Endocrinology Unit of the Mother and Child Centre of the Chantal Biya Foundation in Yaounde, Cameroon from May 2013 to December 2019. All patients diagnosed with a DSD were included, and incomplete files excluded. Results We included 80 patients diagnosed with DSD during the study period. The 46,XX DSD were the most frequent in our study population (n = 41, 51.25%), with congenital adrenal hyperplasia (CAH) as the main diagnosis. The 46,XY DSD accounted for 33.75% and sex chromosome DSD group represented 15% of the study population. Conclusions DSDs are not an exceptional diagnosis in a Sub-Saharan context. 46,XX DSD are the most prevalent diagnosis in our setting. The diagnosis of all these affections is late compared to other centers, justifying advocacy for neonatal screening of DSDs in our context.

The objective of this short communication was the relationship between vitamin D and precocious puberty (PP). In this study, a comprehensive search of multiple databases was performed to identify studies focused on the association between vitamin D deficiency and PP. Studies that compared serum vitamin D levels between patients with PP and controls were selected for the systematic meta-analysis. The main outcome was the mean difference in serum vitamin D levels between PP and controls. Vitamin D-deficient subjects were more likely to develop PP. Our findings suggest that PP may be linked to vitamin D deficiency. Thus, providing supplements of vitamin D to PP patients may improve their nutritional status and prevent diseases. But, the amount of vitamin D required is uncertain, so it is important to be careful when taking vitamin D supplements.

Background Trisomy is a common chromosomal aberration, which usually presents with similar phenotypic abnormalities and developmental delay. Although defined as chromosome abnormalities with recognized symptoms including growth retardation, trisomy 9p and trisomy 14q have been rarely reported to occur at the same time. Case presentation Here, we describe a 16-year-old adolescent female affected by developmental delay and mild intellectual disability. She was confirmed to have both partial trisomy 9p (p24.3-p23) and 14q11.2 microduplication by chromosome microarray analysis (CMA). It is speculated that the extra chromosome in the patient may be a derivative 14 chromosome inherited from the parent after 3:1 disjunction during meiosis. The extra 9p segment proves to be pathogenic while the duplicated 14q11.2 remains indefinite. Conclusions Further studies are needed to assign the genes responsible for the developmental delay and craniofacial dysmorphisms and appoint dosage-sensitive genes of chromosome 9p.

Background Peroxisomal biogenesis disorders (PBDs) include a miscellaneous group of diseases which cause serious multisystem disease. Mutations of 13 different PEX genes lead to PBDs including Zellweger syndrome (ZS). Different types of mutations of PEX1 and PEX10 genes are correlated with broad-range phenotypes of PBDs. Case presentation Patient 1 is a 4-month-old boy who was affected by myoclonic seizures, poor oral feeding since birth. The patient was hypotonic and had hepatosplenomegaly. Patient 2 is a 2-month-old boy who presented with decreased movement, severe hypotonia and failure to thrive. The laboratory studies of the patients revealed increased plasma very-long-chain fatty acids (VLCFAs). The genetic analyses of patient 1 demonstrated the first homozygous missense mutation in the PEX10 gene. A novel homozygous missense mutation was found in the PEX1 gene in patient 2. Conclusions This report highlights that the detected homozygous missense mutations of PEX10 and PEX1 genes and the substitutions of specific amino acids lead to the severe form of PBDs.

We describe four phenotypically different brothers who share the same microduplication of Xq27.1, which contains the SOX3 gene. SOX3 mutations have been associated with growth hormone deficiency, variable degrees of additional pituitary hormone deficiencies, and mental retardation. SOX3 also appears to play an important role in pharyngeal arch segmentation that gives rise to craniofacial structures. While these four brothers have inherited the same mutation, they manifest a spectrum of phenotypes, ranging from complete, multiple pituitary hormone deficiencies to no apparent pituitary hormone deficiency with or without craniopharyngeal/facial dysmorphisms. We look to the literature to provide putative explanations for the variable expression of the brothers’ shared SOX3 mutation.

Background: Gonadotropin-releasing hormone agonists (GnRH-a) are common treatment options for central precocious puberty (CPP) in childhood. GnRH-a treatment is useful and has a good safety profile, with minimal adverse effects and no severe long-term consequences. The common side effects in children are menopause-like symptoms and local adverse events at the injection site. Case presentation: We present the case of a girl with CPP who developed arterial hypertension from treatment with GnRH-a (triptorelin). Comprehensive diagnostic studies ruled out other causes for her hypertension and its complications. After therapy was interrupted, her blood pressure remained within normal limits for age. Consequently, we hypothesize that the hypertension presented by our patient was related to triptorelin treatment. Conclusions: Although the etiology of this adverse event is not known and only some hypotheses can be made, clinicians should be aware that arterial hypertension might appear during triptorelin treatment in childhood with CPP. Therefore, they should routinely monitor the arterial blood pressure of patients under treatment.