Band 29, Heft 6

Thyroid carcinoma is the most common malignancy of the endocrine system and it accounts approximately 1%–3% of all human cancers. Among the three subtypes of thyroid cancers, medullary thyroid carcinoma (MTC) is the most common cause of death in patients with multiple endocrine neoplasia (MEN) type 2A (MEN2A), MEN type 2B (MEN2B) and familial medullary thyroid carcinoma (FMTC). Generally, MTC accounts for up to 10% of all types of thyroid cancers. It is one of the aggressive forms of thyroid carcinoma which is manifested in childhood ages more than adults, and it comprises about 17% of all pediatric thyroid cancer. Like the other cancers, prevention of MTC is easier than its cure. In the recent decades (from 1993) the diagnosis of asymptomatic child carrying RET mutations in the affected families by MTC, has been provided by genetic screening, and prophylactic thyroidectomy is an efficacy therapeutic procedure. On the one hand, according to near the complete penetrance of the disease and its onset in the early years of life, it is required to accelerate the protection of at-risk children with relative affected by MTC and on the other hand, there are several obstructions to MTC treatment including: 1) the proband’s refusal to disclose the RET mutation genetic testing results, 2) children’s vulnerability because of their inability to participate in the informed consent, and 3) the existence of conflict between physicians and children’s guardian. In this review article, the recommendations and ethical issues of MTC treatment in asymptomatic and at-risk children have been summarized.

Background : Serum monocyte chemoattractant protein 1 (MCP-1) and macrophage migration inhibitory factor (MIF) could be involved in the pathophysiological process of diabetes. The aim of the study was to evaluate MCP-1 and MIF in patients with diabetes mellitus type 1 (T1DM) and to assess its relation to diabetic control. Methods: The study included 39 patients with type 1 diabetes and 38 healthy volunteers. Blood sample was taken for assessment of glycosylated hemoglobin, serum MIF and MCP-1. Results : Serum MIF and MCP-1 were significantly higher in diabetic cases than in healthy controls. HbA 1c levels, were significantly higher in cases than in controls. Serum MIF had a significant positive correlation with serum MCP-1 (r=0.361, p=0.03). No other significant correlation with glycosylated hemoglobin or duration of diabetes was detected. Conclusions : A significant increase of serum level of MIF and serum MCP-1 was found in patients with T1DM. These results support that MCP-1 and MIF could be a therapeutic target to treat diabetes and to prevent its complications.

Background: The aim of this study was to assess the prevalence of diabetes and other organ-specific autoantibodies (Ab) associated with various autoimmune conditions, in Polish children with type 1 diabetes mellitus (T1DM). Methods: In this study 114 patients, aged 13.4 years, with mean diabetes duration 5.2 years were included. Ab to islet cell antigens: glutamic acid decarboxylase (GAD), insulinoma antigen 2 (IA-2), zinc transporter 8 (ZnT8), together with thyroid peroxidase Ab (TPO Ab), thyroglobulin Ab (Tg Ab), tissue transglutaminase Ab (tTG Ab) and 21-hydroxylase Ab (21-OH Ab) were measured. Results: The prevalence of at least one diabetes associated Ab was found in 87%, with the highest prevalence of 64% for ZnT8 Ab. In patients with disease duration <5 years, at least one antibody was present in 90%, the most prevalent was ZnT8 Ab (72%). In patients with duration >10 years, 50% had at least one antibody. The prevalence of other than islet cell autoimmunity was high (34%). Thyroid Ab were detected in 26% patients, 42% in girls vs. 8% in boys, p<0.001. tTG Ab were found in 11% patients, with a greater prevalence in children with early onset (p=0.01). 21-OH Ab were found in 2.6% T1DM patients. Conclusions: Islet Ab were found in most T1DM children and remained positive even 10 years after onset. ZnT8 Ab emerged as an important marker for the diagnosis of T1DM in the Polish children. Screening for non-diabetes Ab in T1DM may be helpful in identifying subclinical cases of autoimmune thyroid, celiac or Addison’s disease (AD).

Background: The aim of this study was to investigate seasonality in the initial presentation of type 1 diabetes mellitus (T1DM) among Dutch children. Methods: Observational, nationwide study in the Netherlands. Using the national registry for both healthcare reimbursement and pharmaceutical care, data of all Dutch children (aged 0–14 years) with a diagnosis of T1DM in the period 2009–2011 were obtained. Results: During the study period (2009–2011) an average annual number of 2.909.537 children aged 0–14 lived in the Netherlands and 676 children were diagnosed with T1DM per year, translating into an annual incidence rate (IR) of T1DM of 23.2 per hundred thousand children (ptc). The annual IR differed significantly (p=0.03) between seasons: 6.4 ptc in winter, 4.9 ptc in spring, 5.4 ptc in summer and 6.6 ptc in autumn. This pattern was present within both boys and girls Conclusions: Among Dutch children aged 0–14 years, there is seasonality in the of T1DM with a peak incidence in autumn and winter.

Background: The aim of this study was to evaluate health-related quality of life (HRQOL) in children and adolescents with type 1 diabetes (TIDM) in Montenegro compared with healthy controls and to estimate the effect of metabolic control on perceptions of HRQOL. Methods: This study involved children and adolescents with T1DM, age- and gender-matched healthy children and their parents. Children and adolescents with T1DM and their parents completed Peds QL 4.0 Generic Core Scales (GCS) and PedsQL 3.0 Diabetes Module. Healthy children and their parents completed self- and proxy-report of Peds QL 4.0 GCS. Results: Our study (self- and proxy-report) showed that children and adolescents with T1DM had lower HRQOL on domain “Psychosocial health” and “School functioning” compared with healthy population (p=0.008; p≤0.001). Lower glycosylated hemoglobin (HbA lc ) values were associated with fewer worries, and better health perception by diabetic children and their parents. We did not find notable differences between boys and girls on health perception. Different age groups reported similar QOL. Parents reported that the illness has a greater impact on children’s lives than the children reported themselves. Conclusions: Compared with the healthy children, the HRQOL was lower among children and adolescents with T1DM. Lower HbA 1c was associated with better quality of life.

Background: Fetuin A is an inhibitor of insulin action and have been found to be related with subcutaneous lipid accumulation and insulin resistance. The relation of cardiac lipid accumulation, fetuin A and insulin resistance parameters in obese children is not well-known. The aim of the study was to evaluate the relation of serum fetuin A levels with subcutaneous and cardiac lipid accumulation, and insulin resistance parameters in Turkish obese children. Methods: Serum fetuin A levels, cardiac and subcutaneous lipid accumulation parameters of 42 obese (10.9±2.3 years, 19 female) and 40 control group subjects (11.2±2.7) were compared. Cardiac lipid accumulation measured by subepicardial adipose tissue thickness. Insulin resistance was assessed using homeostasis model assessment (HOMA-IR) index. Results: There were significant correlations serum fetuin A levels with BMI-SDS, circumferences of waist, hip and midarm, SATT and HOMA-IR (r=0.362, p=0.018, r=0.728, p=0.001, r=0.662, p=0.0001, r=0.713, p=0.0001, r=0.477, p=0.001, and r=0.330, p=0.038 as, respectively). Conclusions: Fetuin A was correlated well with cardiac and subcutaneous lipid accumulation, insulin resistance parameters, which may be related with early pathogenetic mechanisms of metabolic obesity complications in children.

Background: The balance between reactive oxygen species production and antioxidant activity has an important role in oxidative stress associated diseases such as phenylketonuria (PKU). We aimed in this study to evaluate the possible association between oxidative balance and clinical features of PKU patients. Methods: Twenty patients and 50 healthy subjects were selected. Prooxidant-antioxidant balance (PAB) was measured and phenylalanine (Phe), tyrosine (Tyr), Phe/Tyr ratio and hematological indices were determined. Results: A significantly higher PAB value was observed in the patient group (152.0±14.1 HK unit) compared to the controls (88.1±13.88 HK) (p<0.05). There was significant correlation between PAB with serum Phe, Tyr, Phe/Tyr ratio, white blood cells (WBC) and red blood cells (RBC) counts. Conclusions: The serum PAB values were higher in patients with PKU and this was associated with the serum Phe and Tyr and Phe/Tyr ratio. Therefore, because of its low cost and simplicity to perform, PAB value might be considered as a useful monitoring marker among the other tools in these patients.

Background: Vaspin (VASP) is a protein detected in pre- and mature adipocytes, the production and secretion of which may be conditioned by nutrition status. VASP may also play a role in the regulation of food intake. Since to date, there are no available studies on serum vaspin concentrations in patients with anorexia nervosa (AN), the aim of our study is to assess serum vaspin concentrations in girls with AN in comparison to healthy subjects and determine its relationship with body weight, body masss index (BMI) and insulin. Methods: In this cross-sectional study vaspin serum concentrations were evaluated using a commercially available ELISA kit in 47 Polish girls hospitalized due to restrictive AN and 39 healthy controls (H). Results: The mean serum concentration of VASP in girls with AN was significantly higher than in the H group. These differences were also noted after adjustment for body masss index-standard deviation score (BMI-SDS), the homeostatic model assessment-insulin resistance (HOMA-IR) index and insulin levels. There were no statistically significant correlations between the serum concentrations of VASP and body mass, BMI, BMI-SDS, insulin and HOMA-IR in the AN or healthy group. Conclusions: Serum vaspin levels in lean subjects are regulated in different mechanisms than previously reported in obesity. It should be established if elevated serum vaspin levels in girls with AN may contribute to low food intake in these patients.

Background: The treatment practices for vitamin D deficiency rickets are highly variable. Though a single intramuscular (IM) megadose of vitamin D is economical, and ensures good compliance, it poses the risk of hypervitaminosis D. This observational study was conducted to assess the duration of effect and safety of single IM megadose of cholecalciferol in the treatment of vitamin D deficiency rickets. Methods: Children younger than 14 years with rickets were enrolled. Baseline investigations included radiograph of wrists and estimation of serum calcium, phosphate, alkaline phosphatase (ALP), 25(OH) vitamin D and parathormone (PTH) levels. All children received a single IM megadose of vitamin D3. Biochemical parameters were re-evaluated at 1.5, 3 and 6 months after the megadose and the values were compared to the baseline. Results: We enrolled 21 children, out of which nine remained under active follow-up till 6 months. Radiological evidence of rickets was present in all 21 children, 14 had hypocalcemia at the time of presentation. After IM cholecalciferol megadose, median 25 hydroxy vitamin D [25(OH)D] level remained significantly more than the baseline till 6 months after the megadose. At 1.5 months after the vitamin D megadose, three (30%) of the children were found to develop toxic levels of vitamin D (>150 ng/mL), although none had hypercalcemia or any clinical manifestation of vitamin D toxicity. At 3 months and 6 months after the megadose, 25(OH)D levels remained in the sufficient range (20–100 ng/mL) in seven out of the eight children who came for follow-up. Conclusions: A single IM megadose of vitamin D may be effective in significantly increasing the 25(OH)D levels for at least 6 months in children with rickets, but elevation of 25(OH)D to toxic range raises concern regarding its safety.

Background: Primary amenorrhea, oligomenorrhea and secondary amenorrhea are diagnosed commonly during adolescence. Weight aberrations are associated with menstrual disorders. Autoimmune thyroiditis is frequent during adolescence. In this study, the commonest clinical and hormonal characteristics of amenorrhea or oligomenorrhea during adolescence were investigated. Methods: In this cross-sectional study, one hundred and thirty-eight consecutive young patients presenting with amenorrhea or oligomenorrhea referred to an adolescent endocrinology and gynecology university clinic were studied. Clinical examination and an abdominal ultrasound were performed. Testosterone, free-testosterone, estradiol (E2), follicle stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL), dehydroepiandrosterone sulfate (DHEA-S), 17-OH progesterone, sex hormone binding globulin (SHBG), Δ 4 -androstenedione (Δ 4 A), free androgen index (FAI), insulin, glucose, thyroid stimulating hormone (TSH), total thyroxine (T4) (TT4), free T4 (FT4), total triiodothyronine (T3) (TT3) and free T3 (FT3). Concentrations were measured in blood samples. Results: Patients with primary and secondary amenorrhea presented more often with body mass index (BMI) <18.5 and BMI >25 kg/m 2 , respectively. BMI values correlated positively with insulin (r=0.742) and glucose (r=0.552) concentrations and negatively with glucose/insulin ratio values (r=–0.54); BMI values and insulin concentrations correlated positively with FAI values (r=0.629 and r=0.399, respectively). In all patients, BMI values correlated positively and negatively with free testosterone (r=0.249) and SHBG (r=–0.24) concentrations, respectively. In patients with secondary amenorrhea insulin concentrations correlated negatively with SHBG concentrations (r=–0.75). In patients with oligomenorrhea BMI values correlated positively with insulin (r=0.490) and TSH (r=0.325) concentrations, and negatively with SHBG (r=–0.33) concentrations. Seventy-two percent, 21% and 7% of patients presented with TSH concentrations <2.5 μIU/mL, between 2.5 μIU/mL, 4.5 μIU/mL and >4.5 μIU/mL (subclinical hypothyroidism), respectively. Following the definition of polycystic ovary syndrome (PCOS) according to either the National Institutes of Health (NIH) criteria or those proposed in the literature by Carmina and his team, patients presented mainly with oligomenorrhea or secondary amenorrhea. There was good agreement between patients with amenorrhea or oligomenorrhea fulfilling both of the PCOS definition criteria employed. Conclusions: Among adolescent patients presenting with amenorrhea or oligomenorrhea for the first time those with low and high BMI present more often with primary and secondary amenorrhea, respectively. Obesity is involved in the development of hyperandrogenemia and hyperinsulinemia, particularly in PCOS patients. In these patients, subclinical hypothyroidism may be concealed and it should be investigated. These patients should be treated for abnormally increased or decreased BMI and be investigated for autoimmune thyroiditis.

Background: Vitamin D is an immune modulator that may play a role in thyroid related autoimmunity. Methods: We analyzed a US population based dataset to determine the relationship between serum 25-hydroxyvitamin D (25OHD) and thyroid hormones while assessing the effects of autoimmunity and BMI. Results: 25OHD did not correlate significantly with any thyroid related measure. 25OHD levels stratified by thyroid antibody status were not statistically different between antibody positive and negative groups. The mean 25OHD levels of lean, overweight, and obese groups defined by BMI were lower than those of the normal group. Only the mean thyroid stimulating hormone (TSH) value in the obese group was significantly higher than the normal group. Conclusions: We conclude that thyroid related measures and 25OHD serum levels are not related.

Background: Ionized calcium (iCa) is believed to be the principle determinant of parathyroid hormone concentration (PTH). However, previous studies contained few infants. Methods: This ancillary study from our vitamin D 3 dose-response trial in healthy, breastfed infants measured calcium, phosphorus, PTH and 25(OH)D (25-hydroxyvitamin D) at 1, 2, 3, 6, 9 and 12 months of age. The relationship between iCa and PTH was assessed by Pearson correlation and a mixed effects regression model to account for repeated measures. Results: No significant correlations were observed between iCa and PTH at individual visits (p>0.2). After accounting for repeated measures, PTH decreased with increasing iCa (slope –5.25; 95% confidence intervals (CI) –8.78 to –1.73), decreased with increasing 25(OH)D (slope –0.006; 95% CI –0.009 to –0.002, and increased with later visits (6–12 months, p<0.001), Conclusions: We observed a weak negative relationship between iCa and PTH and an increase with age consistent with physiologic maturation.

Background: The role of biochemical bone turnover markers (BTMs) in assessing low bone mass and monitoring bisphosphonate treatment in pediatric patients with clinical bone fragility is not well established. The aim of the study was to examine the correlations of BTMs and the bone mineral density (BMD), and evaluate the effects of bisphosphonates therapy on BTMs in children with clinical bone fragility. Methods: Clinical data of 115 patients with clinical bone fragility (mean age 9.7±5.8 years), 102 of whom received bisphosphonates, were studied. Serum alkaline phosphatase (ALP), osteocalcin (OC), urine pyridinoline (PD) and deoxypyridinoline (DPD), BMD at baseline and subsequent years were analyzed. Results: There was a significant negative correlation between urine PD and lumbar BMD (slope=–0.29, p<0.001). There were no correlations between BTMs and lumbar BMD Z-score. There was a significant positive correlation between serum OC and serum ALP, urine PD and DPD (p<0.001). Serum OC, urine PD and DPD index, as expressed as measured value/upper limit of normal value for age, decreased during the first 3 years of bisphosphonate therapy. Conclusions: In children with clinical bone fragility, BTMs correlated with each other, but not with lumbar BMD Z-score. While they were not reliable predictors of degree of low BMD, the bone markers showed suppression during bisphosphonate therapy and may be helpful in monitoring the response to therapy.

Background: We aimed to examine the associations of adipocytokines and circulating bone metabolism markers with bone mineral parameters in early pubertal boys with different physical activity level. Methods: Eighty-six early pubertal boys were divided into active and non-active boys according to the accumulated moderate-to-vigorous physical activity (MVPA) level. Body composition and bone mineral parameters were assessed and testosterone, leptin, adiponectin, osteocalcin (OC), and C-terminal telopeptide of type I collagen (CTX) were measured. Results: Active subjects had significantly lower (p<0.05) body mass, body mass index (BMI), fat mass (FM), leptin, and sedentary time values, while non-active subjects had lower (p<0.05) vigorous physical activity level and femoral neck bone mineral density (FN-BMD). OC contributed to the models in physically active group and explained 6.6% and 9.7% of variance in whole body (WB) [F(5,44)=10.847; p<0.001] and lumbar spine bone mineral content (LS-BMC) [F(5,44)=4.158; p=0.004], respectively. No other biochemical parameters were found to be related to bone mineral parameters in either the active or non-active group. Conclusions: Bone metabolism markers were positively correlated with bone mineral values only in active pubertal boys. Leptin and adiponectin were not related to bone mineral parameters in active and non-active pubertal boys.

Background: In this study, our aim was to analyze bone mineral density (BMD) in patients with type 1 diabetes mellitus (T1DM) and compare them with a healthy reference population; in addition, we aimed to observe the association between BMD and the following variables: age at onset, disease duration, metabolic control, pubertal stage, level of physical activity, clinical parameters and nutrient intake. Methods: A total of 30 patients with T1DM were included in the study. BMD was determined using dual-energy X-ray densitometry (DXA). Participants with a z-score of values ≥–1 were accepted as normal; BMDs between –2 and –1 were defined as being in the low range of normality; ≤–2 were defined as having low BMD. The 25-hydroxy vitamin D level was classified as sufficient (30–100 ng/mL), insufficient (20–30 ng/mL), and deficient (<20 ng/mL). Results: The percentages of patients with deficient and insufficient 25(OH) vitamin D levels were 50% and 45.8%, respectively. Lumbar spine (LS2–LS4) BMD, total body (TB) BMD and femoral neck (FN) BMD were found in the normal range for more than 80% of the subjects, with no significant differences due to gender. No strong correlations between clinical variables, biochemical parameters and nutrient intake were observed; however, a moderate positive correlation was found between serum calcium and LS2–LS4 BMD (p<0.05). Regression analysis showed that serum calcium, duration of diabetes and intake of sodium and protein are significant factors in determining LS2–LS4 BMD and TB BMD. Conclusions: Patients with T1DM had a normal mean BMD at all sites evaluated, except for two patients who had low BMD at the lumbar spine. More than 95% of patients had insufficient or deficient vitamin D levels. With respect to all the variables studied, serum calcium presented the highest significant correlation with LS2–LS4 BMD.

Background: Immunoassays (IAs) are widely used to measure concentration of serum estradiol (E2) despite some limitations including cross-reactivity. Liquid chromatography-tandem mass spectrometory (LC-MS/MS) for E2 measurement has a theoretically greater specificity and sensitivity than IAs. We report a case with unexpected discrepancy in E2 values measured by IA and LC-MS/MS. Case presentation: A 7-year-old girl was referred because of an ovarian tumor. Physical examinations revealed prepubertal statuses. Serum E2 with ECLIA was 69 pg/mL. GnRH stimulation test revealed a prepubertal response. On imaging studies, the diagnosis was mature teratoma of the right ovary. After tumor enucleation, the diagnosis was pathologically confirmed. E2 with ECLIA decreased to 11 pg/mL. Preoperative E2 with LC-MS/MS was 1.15 pg/mL. Conclusions: We conclude the preoperative E2 with ECLIA was falsely high. We speculate the antibody used in ECLIA had cross-reactivity to endogenous compounds. LC-MS/MS should be considered when high serum E2 measured with IA is inconsistent with physical and/or endocrinological data.

Leigh syndrome (LS) is a subacute necrotizing encephalomyelopathy with a diverse range of symptoms, such as psychomotor delay or regression, weakness, hypotonia, truncal ataxia, intention tremor as well as lactic acidosis in the blood, cerebrospinal fluid or urine. Both nuclear gene defects and mutations of the mitochondrial genome have been detected in these patients. Here we report a 7-year-old girl with hypotonia, tremor, developmental delay and psychomotor regression. However, serum lactate level as well as brain magnetic resonance imaging were normal. Mutational analysis has revealed a novel mutation in exon 4 of COX15 gene (c.415C>G) which results in p.Leu139Val. Previous studies have demonstrated that COX15 mutations are associated with typical LS as well as fatal infantile hypertrophic cardiomyopathy. Consequently, clinical manifestations of COX15 mutations may be significantly different in patients. Such information is of practical importance in genetic counseling.

Background: Oral levothyroxine (L-T4) supplementation is usually an effective therapy in pediatric hypothyroidism, except in patients with malabsorption or pseudomalabsorption. In these cases, parenteral L-T4 may be required, but there is a paucity of information about this delivery method in the pediatric population. Case presentation: We present three cases of pediatric patients with primary hypothryoidism unresponsive to oral L-T4 that were successfully treated with intramuscular (IM) L-T4. Conclusions: This is the first pediatric case series of successful IM L-T4 therapy in refractory primary hypothyroidism. Our case series demonstrates that once weekly IM L-T4 dosing may be a safe and well tolerated treatment regimen for pediatric patients.

We characterized a case of congenital adrenal insufficiency caused by cholesterol side-chain cleavage enzyme (P450scc) deficiency. The patient presented after birth with cardiopulmonary instability, hyponatremia, hyperkalemia, hypoglycemia and metabolic acidosis. We confirmed primary adrenal insufficiency. There were no signs of the external genitalia virilism. The replacement therapy with glucocorticoids and mineralocorticoids led to normal laboratory results. At the age of 12 years, we confirmed hypergonadotropic hypogonadism, which revealed disorder of steroidogenesis in the adrenal glands and in the gonads. The enzymatic block was found at the beginning of steroidogenesis. The mutation was confirmed in the CYP11A1 gene. The patient is compound heterozygote for the novel CYP11A1 missense mutation c.412G>A (p.Gly138Arg) in exon 2 and frameshift mutation c.508_509delCT (p.Leu170Valfs*30) in exon 3. The CYP11A1 : c.412G>A (p.Gly138Arg) was predicted as pathogenic by in silico analysis. So far, only 19 patients with CYP11A1 mutations causing P450scc deficiency have been reported worldwide. There are no related reports in the Czech Republic.

Donohue syndrome (DS) is a rare and lethal autosomal recessive disease caused by mutations in the insulin receptor ( INSR ) gene, manifesting marked insulin resistance, severe growth retardation, hypertrichosis, and characteristic dysmorphic features. We describe a new case of Donohue syndrome born at 37 weeks’ gestation of unrelated parents and presented with intra-uterine growth retardation, nipple hypertrophy, macropenis, distended abdomen, hirsutism and dysmorphic features. The clinical course showed failure to thrive, and episodes of alternating hypoglycemia and hyperglycemia. Laboratory tests revealed direct hyperbilirubinemia. The diagnosis of Donohue syndrome was established based on the above clinical characteristics and determination of the INSR mutation. He was found to have homozygous nonsense mutation c. 2270 C>T (Arg924X) at exon 14 of the INSR gene. He later developed enterocolitis and died at 3 months old. Prenatal diagnosis was performed for the family via chorionic villous biopsy. We try to explain gastrointestinal dysfunction seen in our patient.