Band 28, Heft 1-2

Adamantinomatous craniopharyngiomas (ACPs) are histologically benign but clinically aggressive epithelial tumours of the sellar region that are associated with high morbidity and occasional mortality. Research from the last 3 years has provided important insights into the molecular and cellular pathogenesis of these tumours. It has become established that mutations in CTNNB1 (encoding β-catenin), leading to the over-activation of the WNT pathway, underlie the molecular aetiology of human ACP. Interestingly, the effect of these mutations is restricted to a small number of tumour cells, mostly forming clusters, which recent research has shown to be critical for tumorigenesis in mice and humans. Several pathways have been found to be activated in these clusters including the epidermal growth factor receptor and the sonic hedgehog pathways, offering potential therapeutic targets. A novel and unexpected role for pituitary stem cells has been proposed, which is fundamentally distinct from the cancer stem cell paradigm. The study of these benign tumours could reveal important insights into general mechanisms underlying the initial steps of tumorigenesis and facilitate novel tools to improve managements of the patients.

A craniopharyngioma (CP) is an embryonic malformation of the sellar and parasellar region. The annual incidence is 0.5–2.0 cases/million per year and approximately 60% of CP is seen in adulthood. The therapy of choice is surgery, followed by cranial radiotherapy in about half of the patients. Typical initial manifestations at diagnosis in children are symptoms of elevated intracranial pressure, visual disturbances and hypopituitarism. CPs have the highest mortality of all pituitary tumours. The standardised overall mortality rate varies from 2.88 to 9.28 in cohort studies. Adults with CP have a 3–19-fold higher cardiovascular mortality in comparison to the general population. Women with CP have an even higher risk. The long-term morbidity is substantial with hypopituitarism, increased cardiovascular risk, hypothalamic damage, visual and neurological deficits, reduced bone health and reduction in quality of life and cognitive function.

Surgery for craniopharyngiomas, especially in childhood and adolescence, has evolved from an era of aggressive strategies – with the primary goal of gross total removal and accepting an impaired functional outcome – to a more individually tailored therapy that avoids immediate treatment-related and long-term morbidity. Modern imaging techniques and a wider understanding of hypothalamic risk factors have led to surgical strategies adapted to the localization of these inhomogenously grown pathologies. Whereas purely infradiaphragmatic as well as supradiaphragmatic/infrachiasmatic tumors have a favorably surgical outcome with higher gross total resection rates in experienced hands, lesions within the third ventricle extending beyond the mammillary bodies remain a problem. The same is valid for lesions beyond 3 cm in diameter, more or less independent of their localization. Aside from the traditional microscopic approach via the subfrontal or pterional craniotomy, transsphenoidal approaches and other minimal invasive surgical methods, e.g., catheter implantation into cystic formations of the tumor have become popular. Radiotherapy, with its risks and limitations, can effectively be added to avoid recurrences. Nowadays, surgery as part of an interdisciplinary treatment strategy is still the typical first choice. However, taking the patient’s long-term prognosis into considertaion, the surgical complication rates have to be minimized.

Background: As a result of hypothalamic involvement and/or treatment-related hypothalamic damage, up to 75% of childhood craniopharyngioma patients develop hypothalamic obesity. Methods: Eating behavior was analyzed in 101 survivors of childhood craniopharyngioma, recruited from 1980 to 2001 in the HIT-Endo multicenter study, and in 85 body mass index (BMI)-matched healthy controls using the Inventory for Eating Behavior and Weight Problems (IEG) and the Inventory for Eating Disorders (ESI). Results: Severely obese patients (BMI>8 SD; n=9) presented with pathological eating behavior, more weight problems, and eating disorders, as compared to obese (BMI 3–8 SD; n=44) and normal or overweight patients (BMI<3 SD; n=48). Craniopharyngioma patients with different degrees of obesity showed similar or even less pathological findings as compared to BMI-matched normal controls. Conclusion: Severe obesity is associated with pathological eating behavior/disorders in craniopharyngioma patients. As these disorders are not disease-specific, risk factors for hypothalamic obesity should be the focus of further craniopharyngioma research.

Aim: To evaluate auxology and metabolic disturbances in children with craniopharyngioma, and to present observational results of treatment of metabolic sequels with metformin and micronized fenofibrate. Methods: The studied group comprised 22 children [median age at diagnosis 10.5 (0.17–16.75) years; median follow-up 5.1 years]. Assessment included height standard deviations (SDS), body mass index (BMI) SDS, concentrations of lipids, glucose and insulin (fasting or oral glucose tolerance test) and homeostatic model assessment of insulin resistance (HOMA-IR) index. Ten adolescents with hyperinsulinemia and dyslipidemia received therapy with metformin (500–1500 mg/daily) and micronized fenofibrate (160 mg/daily). Results: At diagnosis, median hSDS was –1.66 (range: –4.08; +0.1). Nine (40.9%) children were growth hormone-treated. There was gradual increase of BMI SDS, 18 (81.8%) patients being overweight at the final assessment. Dyslipidaemia was found in 19 patients (86.4%), hyperinsulinaemia in 11 patients (50%) and elevated HOMA-IR in 15 patients (68.2%). Decrease of triglycerides [median 263.5 (171–362) mg/dL vs. 154 (102–183) mg/dL] and HOMA-IR [8.64 (5.08–12.65) vs. 4.68 (0.7–7.9)] was significant in the group treated with metformin and fenofibrate for 6 months. Conclusions: Significant auxologic changes and metabolic abnormalities were found in children treated for craniopharyngioma. The use of metformin and fenofibrate seemed to attenuate these disturbances in a short-term observation.

Objective: Patients treated for childhood craniopharyngioma often develop hypothalamic obesity (HO), which has a huge impact on the physical condition and quality of life of these patients. Treatment for HO thus far has been disappointing, and although several different strategies have been attempted, all interventions had only transient effects. Since thyroid hormones increase energy expenditure metabolism (thyroid hormone induced thermogenesis), it was speculated that treatment with tri-iodothyronine (T3) may be beneficial. In 2002, a case report was published on reduction of body weight after T3 treatment for HO. No studies have been reported since. Recent experimental studies in rodents showed that T3 increases brown adipose tissue (BAT) activity via (pre)sympathetic pathways between the hypothalamus and BAT. Our aim was to investigate whether T3 treatment increases BAT activity in a patient with HO resulting from (treatment of) childhood craniopharyngioma. Methods: Thyroxine treatment for central hypothyroidism was switched to T3 monotherapy. Serum T3 and free thyroxine (FT4) concentrations were measured twice weekly for 2 months. 123 I-MIBG and 18 F-FDG-PET after induction of non-shivering thermogenesis for the assessment of sympathetic and metabolic activity of BAT as well as indirect calorimetry for assessment of resting energy expenditure were performed before and during T3 treatment. Results: No change in sympathetic and metabolic BAT activity, energy expenditure, or BMI was seen during T3 treatment despite the expected changes in thyroid hormone plasma concentrations. Conclusion: We conclude that T3 monotherapy does not seem to be effective in decreasing HO in childhood craniopharyngioma.

Hypothalamic obesity after treatment for craniopharyngioma is a well-recognized, severe problem. Treatment of hypothalamic obesity is difficult and often frustrating for the patient, the parents and the professional care-giver. Because hypothalamic obesity is caused by an underlying medical disorder, it is often assumed that regular diet and exercise are not beneficial to reduce the extraordinarily high body mass index, and in fact, lifestyle interventions have been shown to be insufficient in case of extreme hypothalamic obesity. Nevertheless, it is important to realize that also in this situation, informal care delivered by the family and appropriate parenting styles are required to minimize the obesity problem. We present a case in which weight gain in the home situation was considered unstoppable, and a very early mortality due to complications of the severe increasing obesity was considered inevitable. A permissive approach toward food intake became leading with rapid weight increase since a restrictive lifestyle was considered a senseless burden for the child. By admission to our hospital for a longer period of time, weight reduction was realized, and the merely permissive approach could be changed into active purposeful care by adequate information, instruction, guidance and encouragement of the affected child and her parents. This case illustrates that, although this type of obesity has a pathological origin, parental and environmental influences remain of extreme importance.

Background and aims: The allele variant of neurokinin B and its receptor genes were thought important in regulating the human reproductive axis in many populations. The aim of this study was to investigate whether the variances in TAC3 and TACR3 genes that encoded neurokinin B (NKB) and its receptor (NK3R), individually, were associated with idiopathic precocious puberty in Chinese girls. Methods: The genotyping method of polymerase chain reaction-restriction fragment length polymorphism was applied in this study; the distribution of five active single nucleon acid polymorphisms (SNPs) in TAC3 (p.G34R, p. A63P, p.Q66*, p.S99P, and a mutation on 5′ UTR) and four sites in TACR 3 (A29V or G, G59E, S455G, and A449S or T) genes was analyzed in 267 healthy and 186 idiopathic precocious puberty Chinese girls. Results: Among the nine active SNPs, only A63P in TAC 3 gene showed statistical differences; the p value was 0.024. Conclusion: A63P in TAC3 gene was statistically associated with the puberty onset time in Chinese girls.

Objective: To assess the frequency of incidental findings (IFs) in the population-based “Leipzig Research Centre for Civilization Diseases (LIFE) Child Study” within 1 year. Methods: From July 2011 to June 2012, 969 children participated in the study. The IFs were analysed with respect to age, gender, type of examination and clinical action taken. Results: The IFs were detected in 63 participants (6.5%), including five children who presented with two IFs simultaneously. Eleven children received a new, hence previously unknown, clinical diagnosis. Alternatively, 18 IFs could not be confirmed or were of a transient and self-limiting condition. The frequency of IFs varied widely depending on the type of examination, but did not differ by gender. Conclusion: Although IFs were common events, there was no finding with a profound clinical impact on the subject’s life. Our current IF management protocol may be useful in creating management plans for other cohort studies.

Beckwith-Wiedemann syndrome (BWS) is an overgrowth syndrome caused by multiple epigenetic and genetic changes affecting imprinted genes on chromosome 11p15.5. Hypomethylation of KvDMR1 on the maternal allele is the most common genetic cause, and hyperinsulinaemic hypoglycaemia (HH) is the most common biochemical abnormality. We evaluated the correlation between severity of HH and degree of hypomethylation in BWS. Out of the 19 patients with BWS due to KvDMR1 hypomethylation, 10 patients had no HH, 5 had mild transient HH that resolved spontaneously, and 4 required diazoxide therapy for up to 6 months. There was no correlation between the degree of KvDMR1 hypomethylation and severity of HH in the 6 patients studied. All patients also showed marked clinical heterogeneity with respect to the features of BWS. In patients with BWS due to hypomethylation of KvDMR1, the clinical presentation of HH is quite heterogeneous with no correlation with the degree of KvDMR1 hypomethylation.

Objective: We aimed to obtain the fat base value and the fat distribution characteristics of Tibetan children and teenagers by estimating their body fat content with the bioelectrical impedance method. Methods: We recruited 1427 healthy children and teenagers by a stratified cluster sampling method. By using bioelectrical impedance analysis, we obtained various values relevant to fat. Results: We found that total body fat mass and the fat mass of various body parts increased with age in boys and girls. Yet there were no differences between age groups until 11 years. However, fat mass increased quickly between 11 and 18 years, and significant differences were seen between adolescent boys and girls; all fat indices were higher in girls than in boys (p<0.05). Conclusions: The characteristics of fat in Tibetan children and teenagers in Tibet is related to age and gender related hormone secretion, which reflects the physiological characteristics in different developmental stages.

Objective: With the use of the microarray technique, genes expressed in the late phase of adipocyte differentiation were investigated. These genes play an important role in stimulating adipocyte growth and lipid droplet formation. Therefore, they contribute a great deal to the onset of obesity. Methods: With the use of SW872 adipocytes and the microarray technique, genes related to adipocyte differentiation were tested and compared with undifferentiated preadipocytes 14 days after induction. Real-time reverse transcription polymerase chain reaction (RT-PCR) was used for confirmation. Results: More than 21,329 transcriptors were expressed and determined, of which 1326 increased and 687 decreased undifferentiated adipocytes. Among them, 21 were highly expressed by more than 10-fold. With RT-PCR, 12 were confirmed, including apelin, CIDEC, PID1, LYRM1, ADD1, PPARγ2, ANGPTL4, ADIPOQ, ACOX1, FIP1L1, MAP3K2 and PEX14. Furthermore, genes involved in lipid metabolism, signal transduction, DNA replication, redox status and transcription factors were determined as well. Novel genes involved in adipogenesis (e.g., apelin) were detected. Conclusion: A variety of genes were discovered and validated with RT-PCR at the late phase of adipocyte differentiation. This may help us better understand the onset of obesity and the potential role of adipocytes in other organs.

Background/Aims: Growth hormone (GH) registries indicate that boys receive preferential GH treatment for idiopathic short stature (ISS). The aim was to determine whether age, auxological parameters, pubertal status, and target height differ between genders at GH initiation. Methods: Review of the computerized files of the endocrine department of a tertiary pediatric medical center identified 184 patients who started GH therapy for ISS between 2003–2011. Data on auxologic parameters, predicted height, parental height, and pubertal status were collected and compared between boys and girls. Results: Boys accounted for a significantly higher percentage of the study group (65.8%, p<0.001). At onset of GH therapy, there were no significant differences between boys and girls in age (10.2±3.1 vs. 9.9±2.4 years), height-standard deviation score (SDS) (–2.64±0.5 vs. –2.79±0.5), body mass index-SDS[(–0.65±1.01) vs. (–0.80±1.13)], or pubertal status (66% vs. 63.5% prepubertal). Predicted height-SDS was significantly higher in boys (–1.95±1.05 vs. –2.56±0.73, p<0.001). Midparental height-SDS was similar in the two groups, as were paternal and maternal height. Conclusions: The similar age, height deficit, and pubertal status at onset of GH treatment in boys and girls suggests that gender differences do not exist. Male predominance may stem from family preferences to treat boys. Future studies are warranted to assess the psychosocial aspects in the decision to initiate therapy.

Background : Puberty can affect vitamin D levels. Objectives: The goal of this study was to analyze the relation between vitamin D deficiency and puberty in obese Spanish children, along with the possible interrelation between vitamin D status and degree of insulin resistance. Methods: A cross-sectional study was carried out, in which clinical and biochemical data were gathered from 120 obese and 50 normal weight children between January 2011 and January 2013. Results : Mean vitamin D levels were 19.5 and 31.6 ng/mL in obese pubertal and obese prepubertal children, respectively. About 75% of the obese pubertal subjects and 46% of the obese prepubertal subjects had vitamin D deficiency. Vitamin D levels were significantly lower in pubescent subjects compared with pre-pubescent subjects in summer, fall, and winter. There was no apparent relation between vitamin D levels and homeostasis model assessment index for insulin resistence (expressed in standard deviation score for sex and Tanner stage) in either puberty or pre-puberty. Conclusion : Puberty may be a risk factor for the vitamin D deficiency commonly found in the obese child population. This deficiency is not associated with higher insulin resistance in obese pubertal children compared with obese prepubertal children.

The long-lasting impact of different neglectful environments on growth in children is not well studied. Three groups of children, 3–10 years old, were recruited (n=60): previously institutionalized international adoptees living in stable home environments for at least 2 years (IA; n=15), children with a history of neglect born in the USA (USN; n=17), and controls (n=28). Children underwent physical examination, anthropometry, and collection of serum for growth parameters. Mean height standard deviation scores (SDS) were different (p<0.05). Age-adjusted head circumference (HC) was significantly smaller (p<0.05) in IAs. Insulin growth factor (IGF-1), a marker of growth hormone action, was higher in US neglected children. IGF-1 adjusted for age and weight SDS were different (p<0.05) between control and US neglect groups. The degree of growth failure in height and HC in IAs was more severe than neglected US children. These findings may reflect differences between the impact of chronic and intermittent deprivation on the growth hormone system.

Objectives: Growth hormone deficiency (GHD) is a major problem among children with short stature. In this study, the role of brain magnetic resonance imaging (MRI) in defining the underlying defects among short children with GHD is evaluated. Methods: In a cross-sectional study, data of 158 children were evaluated. Growth hormone (GH) levels were measured using stimulating tests and brain MRI with gadolinium contrast was applied, as well. Results: Some 25.3% of patients had GHD with a mean age of 8.01±3.40 years. MRI results showed 35 as normal, four with pituitary hypoplasia, and one with microadenoma. The MRI results were significantly associated with GH levels and presence of other endocrine disorders. There was a significant association between prenatal disorders and patients’ bone age delay. Conclusions: In patients with severe GHD and patients with multiple pituitary hormone deficiencies, MRI is more likely to be abnormal, and bone age is much delayed in patients with history of prenatal disorders.

Background: Evaluation of lipid profile in children and adolescents is important for early diagnosis of dyslipidemias. Physiological changes might be observed in the concentration of the lipid profile components, according to the stage of sexual maturation. Objective: To evaluate the variation in lipid and lipoprotein concentrations in boys during puberty. Methods: The sample consisted of 570 male adolescents with ages between 10 and 17 years. Weight, height, and body mass index (BMI) were assessed. Total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and triglyceride (TG) were determined by the enzymatic method, and low-density lipoprotein cholesterol (LDL-C) was calculated. Puberty was classified according to Tanner references. The percentile criterion was adopted for the distribution and identification of lipoprotein levels. The analysis of variance and description tests with p<0.05 was applied. Results: Participants had similar BMI z -score and physical activity habits in all groups. A significant reduction in TC and HDL-C concentrations between the start and end of puberty was observed. LDL-C levels rose during stage 3 of development, decreasing at the end of the pubertal process. TG levels did not change significantly with pubertal status. Conclusion: Lipid and lipoprotein concentrations tend to undergo changes during puberty in boys. The use of percentile values can be very useful to track variations in lipid and lipoprotein levels during the maturation process.

Objectives: To compare skin advanced glycation endproducts (AGEs) in children at onset of type 1 diabetes with children without diabetes. Study design: Skin AGEs (sAGEs) were estimated by measurement of skin intrinsic fluorescence (SIF) at diagnosis of type 1 diabetes (NewD; n=47, F=45%, M=55%, Age=10±3.7) and in youth without diabetes (NoD; n=112, F=53%, M=47%, Age=10.4±4.8). HCO 3 , pH, pCO 2 , glucose level, and HbA 1c effect on SIF was evaluated in NewD patients. Results: SIF at 405 nm and 420 nm excitation were higher (p=0.03) in NewD children compared to NoD. HCO 3 , pH, pCO 2 , glucose, and HbA 1c were not associated with SIF levels. Conclusions: Despite the short duration of untreated diabetes, sAGEs were higher in children with NewD compared to children with NoD. Further study will be needed to determine whether early accumulation of sAGEs is associated with higher risk for development and progression of complications.

Background: Optical coherence tomography (OCT) has been proven useful in measuring retinal thickness and volumes in patients with diabetes. Objective: To test whether OCT is able to identify early retinal changes and its potential correlations with metabolic parameters and other microvascular complications. Patients and methods: Thirty patients with type 1 diabetes without minimal diabetic retinopathy (MDR) (17 males, 13 females, aged 14.3±2.4 years) compared with age-matched healthy volunteers were examined with OCT. Diabetes duration, anthropometric measurements, HbA 1c , other microvascular complications (nephropathy, autonomic and peripheral neuropathy) and total serum cholesterol were determined. Results: No statistically significant differences were found between patients with (n=15) and without microvascular complications (n=15) compared to controls regarding retinal volume, nerve fibre layer volume (temporal and nasal quadrants) and ganglion cell layer area in both eyes. No correlation was found between the ganglion cell layer area and the clinical and laboratory characteristics of the patients, except a negative correlation with total serum cholesterol ( r =–0.369, p=0.049). The best cut-off value of ganglion cell layer area to detect the level at which thinning of this layer occurs was >1900 pixels. Conclusion: Our study suggests that there is no advantage in performing OCT routinely in patients with type 1 diabetes mellitus without MDR. OCT did not show changes in retinal thickness in those patients compared to control. So OCT did not seem to be useful in the preclinical stages of diabetic retinopathy. Therefore, the conventional diagnostic methods are mandatory to detect early diabetic retinopathy.

Objectives: To investigate homoarginine and asymmetric dimethylarginine (ADMA) in controls compared to children with type 1 diabetes (T1D) and if homoarginine and ADMA are affected by atorvastatin. Methods: Homoarginine and ADMA levels of 28 T1D patients were compared to levels of 41 controls. In T1D patients, homoarginine and ADMA were determined at baseline, 1 year, and 2 years at daily 10 mg atorvastatin or placebo within a double-blind study. Results: At baseline, both homoarginine and ADMA were lower (p<0.001) in T1D patients compared to controls. In T1D patients, homoarginine and ADMA were not influenced by atorvastatin. Inverse correlations between homoarginine and HbA1c (p<0.001) and between ADMA and systolic blood pressure (p=0.005) and pulse pressure (p=0.003) were shown. Conclusions: Homoarginine and ADMA levels are decreased and associated with cardiovascular risk factors in children with T1D without being affected by atorvastatin.

Background/aims: A rapid catch-up growth in very low birth weight has been associated both with a higher height growth and a higher risk to metabolic disturbances, including insulin resistance and its consequences. Abdominal fat distribution in early postnatal life may play a role in these outcomes and can help in addressing this neonatal dilemma. This study aimed to compare abdominal fat distribution among very low birth weight (VLBW) children with and without rapid catch-up growth. Materials and methods: A cohort study followed 86 VLBW (<1500) children born in Brazil, during the first 3 years of life. Rapid catch-up growth was considered as an increased in length >2 Z score during the first year of life. Abdominal subcutaneous and preperitoneal fat thickness was determined by ultrasound. χ 2 -Test and Student’s t-test were used to compare the groups. Results: A total of 79 VLBW children completed the study, of whom 22 (27.8%) showed rapid catch-up growth. Abdominal subcutaneous and preperitoneal fat thickness showed no differences among children with or without rapid catch-up growth at 3.3 mm vs. 3.8 mm, respectively (p=0.79) and 4.0 mm vs. 4.0 mm (p=0.55), respectively. VLBW children with rapid catch-up growth were also taller. Conclusions: Rapid catch-up growth during the first year of life in VLBW children does not seem to change abdominal fat distribution until the third year of life.

Introduction: Periodic paralysis associated with hyperthyroidism and hypokalemia is an uncommon disorder reported primarily in Asian males and rarely in children. We report three Hispanic adolescent males who were seen with Graves’ disease (GD) and THPP. Methods: The method used was chart review. Results: Two of these boys presented with episodes of paralysis and were diagnosed with GD. The third was initially seen with hyperthyroidism and developed weakness and paralysis when his disease progressed because of therapeutic noncompliance. Hypokalemia was documented in two of the three patients with the third not seen during paralysis. Intravenous K + was required in only one case. All three boys were treated with antithyroid medications and β blockers, and the musculoskeletal symptoms resolved in all three when hyperthyroidism was controlled after 2 weeks of treatment. The duration for each episode of weakness and paralysis varied in each case and resolved within 15 min to 2 h in case 1, 1–5 h in case 2, and 24 h in case 3. Conclusions: THPP is considered uncommon except in Asian males and rare in childhood and adolescence. Its occurrence in these three Hispanic boys suggests that it may occur more frequently in the young and in the USA than has been suspected, especially with the changing national demographics. We believe that our experience should raise the awareness of THPP among pediatric care providers.

Aim: To assess lung function in children and adolescents with type 1 diabetes mellitus (T1DM). Patients and methods: We conducted a case-control study of 100 patients with T1DM [median age 13 (10.6–14.7), 44% men, 23% prepubertal, and all nonsmokers] and 77 controls. None had evidence of lung disease or any other comorbidity. We performed pulmonary function tests, including spirometry [forced vital capacity (FVC), forced expiratory volume in 1 s (FEV 1 ), and FEV 1 /FVC ratio], plethysmography [total lung capacity (TLC), residual volume (RV), RV/TLC ratio, and airway resistance (Raw)], and diffusing capacity of carbon monoxide in the lung (TLCO), alveolar volume (AV), and TLCO/AV ratio. The duration of diabetes, degree of metabolic control, insulin dose, and presence of diabetic complications were registered. The χ 2 -test and analysis of variance were used to compare categorical and quantitative variables, respectively. Results: The duration of diabetes was 6.2±3.8 years with a median HbA 1c of 7.08±0.4%. FEV 1 /FVC ratio was found to be significantly higher in patients with TIDM than in controls. Patients with diabetes also had a nonsignificant trend towards lower FVC, FEV 1 , Raw, and TLCO, and higher RV, TLC, and RV/TLC than controls. There were no differences in pulmonary function based on duration of disease or metabolic control. We found differences in pulmonary evaluation when pubertal stage was analyzed. Conclusions: The lung is functionally involved in children with T1DM. Pubertal development stage influences the evaluation of lung function.

Introduction: Thyroid dysgenesis (TD) is the most common cause of congenital hypothyroidism (CH). Important genetic factors possibly contributing to TD etiologies include mutations of thyroid transcription factors and TSHR-encoding genes. Objective: Our objective was to determine multiplex ligation-dependent probe amplification (MLPA) utility in detecting the copy number changes in patients with CH and TD. Methods : The study included 45 children from southeastern Poland selected via already established neonatal screening for CH. Genomic DNA was extracted from peripheral blood samples and used in MLPA analysis. Genetic variations were analyzed within selected fragments of the PAX8, FOXE1, NKX2-1, thyroid stimulating hormone receptor( TSHR ) , and TPO genes. Results: Three heterozygous deletion types in probe hybridization regions were identified for the following genes: PAX8 (exon 7), TSHR (exon 2), and FOXE1 (exon 1). Monoallelic deletions were identified in 5/45 TD subjects. Conclusions: MLPA is a useful tool for copy number changes detection and might both improve and expand genetic analysis for CH and TD.

Objective: Our objective was to evaluate effects of levothyroxine ( l -T4) supplementation against neurodevelopmental outcomes at 18 months of corrected age in very-low-birth-weight (VLBW) infants with hypothyroxinemia but without elevated thyroid-stimulating hormone (TSH) concentration. Methods: VLBW infants who had plasma TSH concentrations <10 μU/mL and free thyroxine (FT4) concentrations <0.8 ng/dL between 2 and 4 weeks of age were enrolled. They were randomly assigned to either the Treated (n=25) or Untreated group (n=45). The Treated group received l -T4 at a dose of 5 μg/kg/day. We compared growth and neurodevelopmental outcomes at 18 months of corrected age in the two groups. Results: There were no significant differences in growth, the incidences of developmental delay, cerebral palsy, visual impairment, and hearing impairment in the two groups. Conclusions: In such infants, l -T4 supplementation at a dose of 5 μg/kg/day did not affect FT4 levels and showed no beneficial effect at 18 months of corrected age.

Objective : We aim to evaluate how vitamin D-containing supplements affect the vitamin D status of children 1–3 years old and to assess the variation of the vitamin D concentrations across different seasons. Methods-material: This retrospective study included a review of medical reports of 1035 patients (aged 1–3 years) who presented to our hospital between October 2011 and October 2013. The children were divided into 3 groups: Group 1: those supplemented with vitamin D 3 (400 IU/day), Group 2: those supplemented with multivitamins, which included 200–400 IU/day of vitamin D 2 or D 3 , and Group 3, the controls: those not supplemented with vitamin D. The groups were compared as to their biochemical findings and variation of vitamin D status with over four seasons. Results: Gender distribution was not statistically different between the three groups (p=0.38). The children who had taken vitamin D-containing supplements had significantly higher vitamin D levels compared with the children who were given no vitamin D supplementation (p<0.001). Children with no vitamin D supplementation had significantly lower calcium and phosphorus levels compared with Groups 1 and 2. Vitamin D levels were affected by vitamin D supplementation (f=16.125, p<0.001) but not by season (f=0.699, p=0.650). Conclusion: The children aged 1–3 years who did not receive vitamin D-containing supplements had insufficient vitamin D and low levels of calcium and phosphorus. Vitamin D levels were affected by vitamin D supplementation but not by season.

Background: Anti-Mullerian Hormone (AMH), a proposed indicator of ovarian follicle reserve in adults, has not been characterized in pediatric and adolescent females by race and/or ethnicity. Objectives: To describe AMH levels in healthy American girls and determine the influence of age and race/ethnicity on AMH. Subjects: Subjects aged 10–21 years were recruited from primary care settings and emergency departments. Race/ethnicity was characterized as White, Black or Hispanic. Methods: Serum for AMH levels (ng/mL) was measured using an enzyme-linked immunosorbent assay. Results: Thirty-one White, 60 Black and 24 Hispanic subjects were recruited. Mean AMH levels were 3.19 ng/mL (22.8 pmol/L) (SD 2.12) for Whites, 3.25 ng/mL (23.2 pmol/L) (SD 2.23) for Blacks and 2.97 ng/mL (21.2 pmol/L) (SD 1.75) for Hispanics. ANCOVA showed no difference in AMH levels among race/ethnicities, controlling for age (p=0.91). Age was significantly associated with AMH (p<0.001, R 2 =0.12). Conclusion: AMH levels do not vary by race/ethnicity, and AMH levels increase with age.

Aim: To determine the individual fasting tolerance for patients with glycogen storage disease type III (GSD III) and to assess their linear growth velocity after tailoring of dose intervals of oral uncooked cornstarch. Patients and methods: A prospective cohort study included 32 patients with GSD III aged 6 months–11.5 years (median: 3.3 years). The fasting tolerance of each patient was determined as the time interval between starch administration until the drop in blood glucose level was below 60 mg/dL. Results: Some 27 patients (84.4%) developed hypoglycemia. The intervals between oral cornstarch administration were tailored for each child according to his/her individual fasting tolerance. After a 6-month follow up there was a significant reduction in seizure attacks (p<0.01) and liver size (p<0.01), but there was no statistically significant difference in liver transaminase and serum lactate levels. There was a significant improvement in height (p<0.01) and linear growth velocity (p<0.05) of these patients after at least a 12-month follow up. Conclusion : Adjusting the intervals between the cornstarch doses for each patient with GSD III, according to individual fasting tolerance test was very beneficial and resulted in improvement of the linear growth velocity and reduction in the frequency of hypoglycemic seizures as well as the size of the liver. Individual scheduling of cornstarch doses prevents complications in those who develop hypoglycemia at short intervals; it also allows some relaxation in schedule for those who can tolerate longer fasting hours to improve their appetite and prolong their uninterrupted sleep hours.

Aim: The aim of this study was to determine the prevalence of autoimmune thyroid disease in Turner syndrome (TS) and the association between thyroid autoantibodies (TAA), thyroid dysfunction, age, and karyotype. Methods: Sixty-nine girls with TS were divided into two groups according to being TAA-positive or TAA-negative. TAA and thyroid hormone concentrations were determined by immunochemiluminescence. Results: One third (23/69) of the girls were TAA positive, with antibody prevalence increasing with age. Of the TAA-positive girls, seven were hypothyroid and three hyperthyroid. Compared with the TAA-negative group, the girls in the TAA-positive group were significantly older (p<0.05). For those who were TAA positive, 26.3% of patients were 5–10 years old, 37.1% 10–15 years old, and 62.5% above the age of 15 years. Conclusion: Chinese girls with TS are prone to Hashimoto’s thyroiditis, especially those older than 5 years, and routine thyroid testing is advocated thereafter on a yearly basis. There was no specific association between the incidence of autoimmune thyroid disease and TS karyotypes.

46,XY complete gonadal dysgenesis (Swyer syndrome) is a rare cause of disorder of sexual development. This syndrome is caused by a defect in the determination of sex during embryogenesis and is characterised with female external genitalia, normal or rudimentary uterus, and streak gonads, despite the presence of the 46,XY karyotype. Most of the studied cases presented with leak of secondary sex characteristics and primary amenorrhea during adolescence. Laboratory findings reveal hypergonadotropic hypogonadism. Herein we present the case of a female with a 46,XY karyotype who was admitted with delayed puberty and detected to have a microdeletion in the SRY gene and diagnosed to have Swyer syndrome. We highlight the importance of karyotype analysis in patients with delayed puberty and primary amenorrhea. Once the diagnosis of 46,XY complete gonadal dysgenesis is established, early laparoscopic removal of the dysgenetic gonads is crucial to prevent the development of gonadal malignancy.

X-linked hypophosphatemic rickets (XLH) is the most common inherited form of rickets. XLH is caused by inactivating mutations in the PHEX gene and is transmitted as an X-linked dominant disorder. We investigated PHEX mutation in a sporadic Turkish girl with hypophosphatemic rickets. The patient was 2 years of age with a complaint of inability to walk. She had bowing of legs and growth retardation. Laboratory data showed normal calcium, low phosphate with markedly elevated ALP, and low phosphate renal tubular reabsorption. She was treated with Calcitriol 0.5 mg/kg/day and oral phosphate supplement with good response. The entire coding region of PHEX gene was sequenced from patient’s peripheral leukocyte DNA and a novel 13 bp deletion at the donor splice site of exon5 was found (c.663+12del). Instead of using the donor splice site of intron 4 to splice out exon 5 and intron 5, the spliceosome utilized two nearby cryptic donor splice sites (5′ splice site) to splice out intron 4, resulting in two smaller transcripts. Both of them could not translate into functional proteins due to frameshift. Her parents did not carry the mutation, indicating that this is a de novo PHEX mutation likely resulting from mutagenesis of X chromosome in paternal germ cells. We conclude that c.663+12del is a novel mutation that can activate nearby cryptic 5′ splice sites. The selection of cryptic 5′ splice sites adds the complexity of cell’s splicing mechanisms. The current study extends the database of PHEX mutation and cryptic 5′ splice sites.

Infants born small for gestational age (SGA) are at risk to develop metabolic complications. Insulin-like growth factor 1 (IGF-1) resistance due to IGF-1 receptor (IGF1R) mutations is a rare genetic condition that causes proportionate growth retardation. The contribution of an impaired IGF1R function to the development of comorbidities such as disturbed glucose homeostasis is not well understood. Genetic analysis and detailed auxological, endocrine and psychological investigations in two male SGA siblings were performed. The two patients and their father bear a novel heterozygous mutation (p.Cys1248Tyr) in the IGF1R gene. Both brothers displayed very similar growth pattern before and during recombinant human growth hormone treatment, whereas oral glucose tolerance tests showed variable manifestations of progressive impaired glucose tolerance. The father had already developed type 2 diabetes mellitus. Growth retardation in our patients is likely caused by the IGF1R mutation that might predispose to disturbances of carbohydrate homeostasis. Therefore, a close metabolic monitoring of affected patients is indicated, particularly if growth hormone therapy is commenced.

On average, ectopic thyroids are positioned in the embryotic decent path that emerges as a lingual thyroid or a thyroglossal duct cyst. It is uncommon for ectopic thyroids to be located in the lateral neck, which only represents 1%–3% of all cases. Any ectopic thyroids that emerge in the posterior lateral neck in pediatric patients should be regarded as an extremely unique case. We report a 13-year-old boy with ectopic thyroid tissue in the cervical lymph nodes with orthotopic euthyroid thyroid. The masses were located on the left posterior triangle area, which were confirmed as histologic benign thyroid tissue without any malignancy in the head and neck. Authors suggest that this case supports the benign lymphatic transport theory of lateral ectopic thyroid.

Hyperostosis-hyperphosphatemia syndrome (HHS) is a rare autosomal recessive metabolic disorder caused by mutations in the GALNT3 and FGF23 genes. The main features of this disorder include painful swelling of long bones, increased renal reabsorption of phosphate but normal renal function and vitamin D and parathormone levels. Previously, we reported a novel missense mutation in the FGF23 gene in a patient suffering from HHS. In the present report, we demonstrated the same mutation (c.471C>A) in two other cases of HHS with similar clinical manifestations. As this nucleotide change has not been reported previously, it can be a population specific mutation in Iran that can facilitate carrier testing and prenatal diagnosis of HHS.

We report on two young children with type 1 diabetes mellitus, treated by continuous subcutaneous insulin infusion, who developed severe hyperglycaemia and detachment of the needle from the insulin infusion set.

Here we report the case of a young girl who had vague signs and symptoms potentially attributable to hyperthyroidism and was found to have autoimmune thyroiditis and hyperthyroxinemia. The elevated serum free thyroxine levels were persistent when measured by both standard assays and equilibrium dialysis/high-pressure liquid chromatography-tandem mass spectrometry. The clinical symptoms, with discordant thyroid test results, created a diagnostic dilemma that led initially to unnecessary additional evaluations. She was ultimately found to have familial dysalbuminemic hyperthyroxinemia (FDH) and required no therapy. This case highlights the inherent difficulties in evaluating children, who typically have vague signs and symptoms of thyroid dysfunction, when, in addition, they have an unrelated acquired (autoimmune) as well as a genetic (FDH) defect. The benefit of including testing for immediate members of the family is emphasized.