Band 27, Heft 11-12

Cushing syndrome is caused by prolonged exposure to elevated serum cortisol. It is uncommon in children, and etiology includes pituitary adenoma, adrenal tumor, and exogenous glucocorticoid administration. Rarely, it is paraneoplastic in origin. We present a case of paraneoplastic Cushing syndrome due to Wilms tumor that secreted corticotropin-releasing hormone (CRH). A 6-year-old male presented with polyphagia and weight gain. He showed Cushingoid appearance, hypertension, and palpable left flank mass. Serum cortisol and adrenocorticotropic hormone (ACTH) levels were elevated. Computed tomography showed a neoplasm originating from the left kidney. Pathologic diagnosis of Wilms tumor was made upon nephroureterectomy. Immunohistochemical staining was positive for CRH and negative for ACTH. All features of Cushing syndrome disappeared after surgery. This represents a rare case of Cushing syndrome secondary to Wilms tumor in which CRH production has been demonstrated.

Here we report an adolescent male with Cushing’s disease secondary to a pituitary adenoma who was admitted with cholestatic hepatitis. A detailed work-up for hepatitis was negative except for a novel heterozygous ABCB4 gene mutation encoding multidrug resistance type III (MDR3) protein. Upon resection of the pituitary adenoma, the hepatic biochemical abnormalities gradually improved. This case highlights that heterozygous ABCB4 defect may represent a genetic predisposition for nongenetic factors such as hormones or other metabolites to decrease normal MDR3 allele expression. It is known to act as a modifier gene and possibly played a role in the development of cholestatic hepatitis and cholelithiasis, in the presence of excess cortisol secondary to Cushing’s disease in our patient.

Background: Cushing’s disease is very rare in children, and the diagnosis is frequently delayed by several years. Objective: We report a case of prepubertal Cushing’s disease with a medical history of only 9 months. This case illustrates the difficulties involved in diagnosing children at the early stage of the disease. Case presentation: An 8-year-old prepubertal boy presented with rapid weight gain accompanied by a decreasing growth velocity and hirsutism. Thyroid function tests and growth factor levels were normal, thus excluding hypothyroidism and growth hormone deficiency. Cushing’s syndrome was confirmed by elevated 24-h urinary free cortisol levels, increased diurnal cortisol levels, and a lack of cortisol suppression in the low-dose dexamethasone suppression test. Further tests to investigate the source of the hypercortisolism showed the following results: Basal morning adrenocorticotropic hormone (ACTH) was normal. The high-dose dexamethasone suppression test led to a 51% decrease in cortisol level. In the corticotropin-releasing hormone (CRH) test, ACTH and cortisol increased only by 28%. Repeated magnetic resonance imaging (MRI) finally revealed a microadenoma in the anterior pituitary, thus establishng the diagnosis of Cushing’s disease. Upon diagnosis, the patient underwent transsphenoidal surgery. Histological analysis confirmed an ACTH-secreting pituitary adenoma. Conclusion: This case illustrates the difficulties associated with the clinical, biochemical, and radiological diagnoses of Cushing’s disease in children. Early diagnosis remains a challenge because test results often do not match standard diagnostic criteria.

Subclinical hypothyroidism (SH) is defined as a serum thyroid-stimulating hormone (TSH) level above the reference range with normal serum free thyroxin (sT4) and free triiodothyronine (sT3) levels. The prevalence of SH in children and adolescents is reported between 1.7% and 9.5%. Hashimoto’s thyroiditis is the most prevalent cause of SH in children. Although it has been suggested that SH is entirely an asymptomatic laboratory diagnosis, typical hypothyroid symptoms as well have been reported in some patients. Results of the adult studies on SH revealed that SH had unfavorable effects on cardiovascular system (atherosclerosis); metabolic parameters (dyslipidemia, insulin resistance, etc.); neuromuscular system; and cognitive functions in the long term. The number of studies investigating the effect of childhood SH on growth, bone maturation, lipid parameters, carbohydrate metabolism, neuromuscular system, and cognitive and cardiac function is limited. Knowledge about the natural history of SH is unclear even though there are numerous studies upon this subject. In children and adults, treatment of SH with L-T 4 is still a matter of debate, and there is no consensus on this issue yet.

Pyruvate dehydrogenase (PDH) deficiency is an inherited disorder of carbohydrate metabolism, resulting in lactic acidosis and neurological dysfunction. In order to provide energy for the brain, a ketogenic diet has been tried. Both the disorder and the ketogenic therapy may influence energy production. The aim of the study was to assess hepatic glucose production, lipolysis and resting energy expenditure (REE) in an infant, given a ketogenic diet due to neonatal onset of the disease. Lipolysis and glucose production were determined for two consecutive time periods by constant-rate infusions of [1,1,2,3,3- 2 H 5 ]-glycerol and [6,6- 2 H 2 ]-glucose. The boy had been fasting for 2.5 h at the start of the sampling periods. REE was estimated by indirect calorimetry. Rates of glucose production and lipolysis were increased compared with those of term neonates. REE corresponded to 60% of normal values. Respiratory quotient (RQ) was increased, indicating a predominance of glucose oxidation. Blood lactate was within the normal range. Several mechanisms may underlie the increased rates of glucose production and lipolysis. A ketogenic diet will result in a low insulin secretion and reduced peripheral and hepatic insulin sensitivity, leading to increased production of glucose and decreased peripheral glucose uptake. Surprisingly, RQ was high, indicating active glucose oxidation, which may reflect a residual enzyme activity, sufficient during rest. Considering this, a strict ketogenic diet might not be the optimal choice for patients with PDH deficiency. We propose an individualised diet for this group of patients aiming at the highest glucose intake that each patient will tolerate without elevated lactate levels.

Aim: We describe the novel clinical observation of protein induced hyperinsulinaemic hypoglycaemia following remission of transient neonatal diabetes mellitus (TNDM) in a patient with 6q24 methylation defect. Methods: A male infant of non-consanguineous Caucasian parents, born at 40 weeks of gestation with a birth weight of 3330 g (–0.55 standard deviation score) presented with hyperglycaemia in the first week of life and was diagnosed with 6q24 TNDM. At 22 months of age, he developed recurrent hypoglycaemic episodes. Controlled diagnostic fast, oral glucose tolerance test, protein loading test and mixed meal tolerance test were undertaken. Sequencing of ABCC8 , KCNJ11 , GLUD1 and HADH were performed. Results: Investigations suggested a diagnosis of protein sensitive hyperinsulinaemic hypoglycaemia with normal serum ammonia, acylcarnitine profile and urine organic acids. Sequencing of ABCC8 , KCNJ11 , GLUD1 and HADH did not identify a pathogenic mutation to explain his hyperinsulinaemic hypoglycaemia. Conclusion: This clinical case demonstrates the novel observation of protein sensitive hyperinsulinaemic hypoglycaemia in a patient with 6q24 TNDM. Long-term follow-up of patients with chromosome 6q24 TNDM is warranted following remission.

Objective: The aim of this study is to provide normative data about pituitary diameters in a pediatric population. Pituitary imaging is important for the evaluation of the hypothalamo-pituitary axis defect. However, data about normal pituitary gland diameters and stalk are limited, especially in children. Structure and the measurements of pituitary gland and pituitary stalk may change due to infection, inflammation, or neoplasia. Methods: Among 14,854 cranial/pituitary gland magnetic resonance imaging scans performed from 2011 to 2013, 2755 images of Turkish children aged between 0 and 18 were acquired. After exclusions, 517 images were left. Four radiologists were educated by an experienced pediatric radiologist for the measurement and assessment of the pituitary gland and pituitary stalk. Twenty cases were measured by all radiologists for a pilot study and there was no interobserver variability. Results: There were 10–22 children in each age group. The maximum median height of the pituitary gland was 8.48±1.08 and 6.19±0.88 mm for girls and boys, respectively. Volumes were also correlated with gender similar to height. Minimum median height was 3.91±0.75 mm for girls and 3.81±0.68 mm for boys. The maximum and minimum pituitary stalk basilar artery ratios for girls were 0.73±0.12 and 0.59±0.10 mm. The ratios for boys were 0.70±0.12 and 0.56±0.11 mm. Conclusion: Our study demonstrated the pituitary gland and stalk size data of children in various age groups from newborn to adolescent. It is thought that these data can be applied in clinical practice. Future prospective follow-up studies with larger samples, which correlate the structural findings with the clinical and laboratory results are awaited.

Background: We sought to disentangle the contributions of hyperthyrotropinemia (an indicator of thyroid dysfunction) (HTT) and intermittent or sustained systemic inflammation (ISSI) to structural and functional indicators of brain damage. Methods: We measured the concentrations of thyroid-stimulating hormone (TSH) on day 14 and of 25 inflammation-related proteins in blood collected during the first 2 postnatal weeks from 786 infants born before the 28th week of gestation who were not considered to have hypothyroidism. We defined hyperthyrotropinemia (HTT) as a TSH concentration in the highest quartile for gestational age on postnatal day 14 and ISSI was defined as a concentration in the top quartile for gestational age of a specific inflammation-related protein on 2 separate days a week apart during the first 2 postnatal weeks. We first assessed the risk of brain damage indicators by comparing 1) neonates who had HTT to those without (regardless of ISSI) and 2) neonates with HTT only, ISSI only, or HTT+ISSI to those who were exposed to neither HTT nor ISSI. Results: In univariable models that compared those with HTT to those without, HTT was not significantly associated with any indicator of brain damage. In models that compared HTT only, ISSI only, and HTT+ISSI to those with neither, children with ISSI only or with HTT+ISSI were at significantly higher risk of ventriculomegaly [odds ratios (ORs) 2–6], whereas those with HTT only were at significantly reduced risk of a hypoechoic lesion (ORs 0.2–0.4). Children with HTT only had a higher risk of quadriparesis and those with ISSI alone had a higher risk of hemiparesis (ORs 1.6–2.4). Elevated risk of a very low mental development score was associated with both ISSI only and HTT+ISSI, whereas a very low motor development score and microcephaly were associated with HTT+ISSI. Conclusions: The association of HTT with increased or decreased risk of indicators of brain damage depends on the presence or absence of ISSI.

Objectives: Given that tricho-rhino-phalangeal syndrome (TRPS) and pseudohypoparathyroidism/pseudopseudohypoparathyroidism (PHP/PPHP) are very rare monogenic disorders that share some features (distinctive facies, short stature, brachydactyly and, in some patients, intellectual disability) that lead to their misdiagnosis in some cases, our objective was to identify clinical, biochemical or radiological signs that could help to distinguish these two syndromes. Methods and results: We report on two cases, which were referred to the Endocrinology and Pediatric Endocrinology Services for obesity. Clinical evaluation initially suggested the diagnosis of PHP-Ia [phenotype suggestive of Albright hereditary osteodystrophy (AHO) with parathyroid hormone (PTH) resistance] and PPHP (phenotype resembling AHO, without PTH resistance), but (epi)genetic analysis of the GNAS locus ruled out the suspected diagnosis. Further clinical re-evaluation prompted us to suspect TRPS, and this was confirmed genetically. Conclusion: TRPS was mistakenly identified as PHP/PPHP because of the coexistence of obesity and brachydactyly, with PTH resistance in one of the cases. Specific traits such as sparse scalp hair and a pear-shaped nose, present in both cases, can be considered pathognomonic signs of TRPS, which could help us to reach a correct diagnosis.

The objective of this study was to determine the extent to which constitutive skin color explains racial/ethnic differences in serum 25-hydroxyvitamin D (25OHD) concentrations in urban schoolchildren. Analysis of covariance (ANCOVA) was used to determine associations of 25OHD with parent-reported race/ethnicity and constitutive skin color as measured by reflectance colorimeter [individual typology angle (ITA°; higher value corresponds to lighter skin)] in 307 Greater Boston schoolchildren aged 9–15 during October–December 2011. Nearly 60% of all children were inadequate in 25OHD (<20 ng/mL). Prevalence of inadequate 25OHD differed by race/ethnicity (p<0.001): white (46.6%), black (74.5%), Hispanic (64.7%), Asian (88.9%), and multi-racial/other (52.7%). Serum 25OHD increased 0.6 ng/mL per 10° increase in ITA° value (p<0.001). The prediction of 25OHD by race/ethnicity was slightly stronger than the prediction by skin color in separate models (R 2 =0.19, R 2 =0.16, respectively). Most of the variability in 25OHD in race/ethnicity was due to constitutive skin color in this group of racially diverse US children.

Congenital hypothyroidism (CH), one of the most important preventable causes of mental retardation, is a clinical condition characterized by thyroid hormone deficiency in newborns. CH is most often caused by defects in thyroid development leading to thyroid dysgenesis. The thyroid-stimulating hormone receptor (TSHR) is the main known gene causing thyroid dysgenesis in consanguineous families with CH. In this study, we aim to determine the genetic alteration in a case with congenital hypothyroidism and heart defects coming from a consanguineous family. We utilized genetic linkage analysis and direct sequencing to achieve our aim. Our results revealed that the family showed linkage to the TSHR locus, and we detected a homozygous nonsense mutation (R609X) in the case. Apart from other cases with the same mutation, our case had accompanying cardiac malformations. Although cardiac malformations are not uncommon in sporadic congenital hypothyroidism, here, they are reported for the first time with R609X mutation in a familial case.

Objectives: The aim of this study is to identify factors accounting for the variation in 25-hydroxyvitamin D levels in a pediatric obese population. Patients and Methods: One hundred and forty-nine obese children and adolescents (BMI ≥95th percentile) were evaluated in a pediatric endocrine office. Acanthosis nigricans (AN) skin lesions were rated on a 4-point scale. Results: The 25-hydroxyvitamin D levels were significantly different between those without AN and those with any severity of AN (p=<0.001). Insulin levels were only significantly different between those with no and severe AN (p=0.007). A general linear model showed that month of visit predicted 19.0% of the variation and AN an additional 2.2%. When AN was dropped from the full model, log-transformed HOMA-IR remained insignificant (p=0.164). Conclusions : Season of evaluation was the main determinant of 25-hydroxyvitamin D levels. Severity of AN was a stronger predictor of 25-hydroxyvitamin D level variation than the measure of insulin resistance HOMA-IR.

Background: Silver-Russell syndrome (SRS) is an imprinting defect disease. This is the first study of Chinese children with SRS caused by chromosome 11p15 imprinting defects. Methods : Twenty-five SRS cases, diagnosed in Beijing Children’s Hospital from 2006 to 2012, were studied retrospectively to detect chromosome 11p15 imprinting defects. Results: Over 80% of the children had (i) small for gestational age and postnatal growth retardation (mean height standard deviation score [HT SDS] was –3.56), (ii) mean body mass index (BMI) SDS was –2.10, and (iii) skeletal malformation. Chromosome 11p15 imprinting defects were examined in 16 of the 25 patients. Six had hypomethylation in chromosome 11p15 imprinting control region 1 (ICR1) of the paternal allele; one had hypomethylation in chromosome 11p15 ICR1 and hypermethylation in imprinting control region 2 (ICR2). Another patient had a duplicated maternal chromosome 11p15 fragment. Six patients had been treated with for 3–24 months. Growth rates ranged from 4 to 10.8 cm/year. Conclusions: This study demonstrated that Chinese children with SRS had more growth retardation than bone retardation, severely low levels of BMI, triangular faces, and limb asymmetry. Chromosome 11p15 imprinting defects contributed to 50% of these cases, and ICR1 hypomethylation was associated with asymmetry.

Background: This aim of this study was to update information on body mass index (BMI) references and prevalence of overweight and obesity in Turkey, and to compare our data with previous local and international data. Methods: This cross-sectional study was carried out in Turkish school-age children living in Kayseri, Turkey in 2008. BMI references were calculated and the prevalence of overweight and obesity was determined. Growth curves were produced and compared with concomitant (4 years ago) local and international data. Results: A total of 4241 children (2339 girls and 1902 boys) aged 6–18 years were included. The 5th and 50th percentiles of boys in the current study were approximately 0.8–1.2 units lower than those reported previously. The 95th percentile in our study was higher than those found in previous studies. The prevalence of obesity and overweight was found to be higher in the current study when compared with a previous study (3.9%–4.5% and 15.4%–18.0%, respectively). In the current study, obesity was found to be increased in boys (4.8%–5.4%) but decreased in girls (4.8%–3.5%) when compared with a previous study. We found that our BMI references were significantly higher until 15–16 years of age for the 85th and 95th percentiles compared with World Health Organization standards. Conclusions: This study provides information on updated BMI references and the prevalence of overweight and obesity. The prevalence of overweight and obesity should be screened in short periods. In the evaluation of overweight and obesity, international standards and local references should be evaluated together.

Background: Remission rates with antithyroid drugs (ATDs) in pediatric Graves’ disease (GD) are low. Very few studies report long-term follow-up of GD especially into adulthood. Objectives: We studied long-term outcomes of pediatric onset GD, including a follow-up into adulthood and factors associated with need for definitive therapy. Methods: Sixty-five patients (57 females) with GD, with onset <18 years (median 13, range, 3.5–17) and duration ≥2 years (median 7; range, 2–22) since diagnosis, were included. Medical records were reviewed, and current details were recorded in a questionnaire by telephonic interview. Results: All patients were initially treated with ATDs. Fifty-three patients were treated for ≥2 years. Amongst these, outcomes included relapse after initial remission (n=38), failure of remission (n=8) and long-term remission, defined as remission lasting ≥4 years (n=6). One patient had carbimazole and surgery but died of hepato-renal failure secondary to systemic vasculitis. A total of 44/65 patients were managed with definitive treatment. Those needing definitive treatment had higher mean free T4 (54.6±23.7 vs. 39.5±20.5 pmol/L, p=0.02) and thyrotropin receptor antibody (TRAB) titers (34.1±19.3 vs. 13.8±9.9 IU/L p<0.0001). Long-term sequelae included need for thyroxine replacement (n=42, 64.6%), persistent goiter (12/62, 19.3%) and persistent ophthalmopathy (19/40, 47.5%). Conclusions: Long-term remission rates of pediatric onset GD with ATDs are very low, especially with longer follow-up. Higher pretreatment free T4 and high TRAB titers predict need for definitive treatment.

Background: Diabetic ketoacidosis (DKA) is a life-threatening condition occurring in patients with newly developed type 1 diabetes. Objective: To investigate the factors associated with the risk of DKA and the duration of diabetic symptoms reflected by glycated hemoglobin (HbA1c) level. Methods: The study group included 652 children admitted to our department with newly diagnosed diabetes. Clinical data were collected from available medical records. The distance between the patient’s house and the hospital was calculated using a Google Maps-based distance calculator. Results: Ketoacidosis of any severity was present in 189 patients (30.14%). The mean HbA1c level at admission was 11.76%±2.57%. Children admitted directly to the specialist center were less likely to develop DKA: odds ratio (OR) (95% confidence interval, 95% CI)=0.45 (0.26–0.78). Older age exerted a protective effect: OR (95% CI)=0.92 (0.87–0.96). Patients living farther from the center had higher HbA1c levels: β (95% CI)=0.10 (0.01–0.18). Having a parent with diabetes promoted an earlier diagnosis of diabetes, as evidenced by lower HbA1c: β (95% CI): –0.18 (–0.27 to –0.96) and marginally lower risk of DKA: OR (95% CI)=0.50 (0.22–1.12). Conclusion: Rapid transfer to the specialist center plays a crucial role in the prevention of DKA.

Background: Low vitamin D [25(OH)D] levels have been associated with type-2 diabetes mellitus. Children born large for gestational age (LGA) may exhibit increased indices of insulin resistance early in life. Objective: This study aims to prospectively examine serum 25(OH)D and parathormone (iPTH) levels in LGA and appropriate for gestational age (AGA) prepubertal children, in relation to the severity of macrosomia and insulin resistance. Methods: Children were examined at age 5–7.5 years, 38 born LGA and 39 AGA, matched for age, gender, body weight, height and body mass index (BMI). Twenty-one LGA had birth weights in the 90th–97th percentile and 17 >97th percentile. Fasting serum levels of glucose, insulin, 25(OH)D, and iPTH were measured. The homeostasis model assessment for insulin resistance (HOMA-IR) was estimated. Results: The insulin resistance indices were higher in the LGA >97th percentile subgroup than in the AGA group: HOMA-IR 1.53±0.66 vs. 1.04±0.53 and fasting insulin 6.92±3.1 vs. 4.78±2.2 μIU/mL (but similar to the AGA group), and in the LGA 90th–97th percentile subgroup: HOMA-IR 1.17±0.61 and insulin 5.53±2.2. There was no difference in 25(OH)D among the three subgroups. The iPTH was higher in the LGA >97th percentile subgroup than in the AGA group (26.8±7.6 and 22.6±7.2 pg/mL, respectively, p<0.05), although it was not correlated with insulin resistance indices. Birth weight was correlated negatively with fasting insulin and HOMA-IR in the entire cohort, independent of age, sex, waist circumference, and BMI (β=0.37, p<0.01 and β=0.30, p<0.05, respectively), while waist circumference was positively correlated with HOMA-IR (R=0.40, p<0.001). Conclusion: Birth weight and current body composition appear to affect glucose homeostasis in LGA prepubertal children, while the serum levels of 25(OH)D and iPTH appear to be uninvolved.

Background: The data on the prevalence of vitamin D deficiency (VDD) in apparently healthy children from India is limited. Objective: To assess the prevalence of VDD in apparently healthy children. Design: Prospective study. Setting and subjects: Apparently healthy children from the age groups of 3 months–12 years, from the upper socioeconomical status (USES), attending the outpatient department (OPD) of a private pediatric hospital in Chandigarh, India, for minor ailments were enrolled over a period of 6 months (March–August 2013). Methods: Plasma levels of 25-hydroxyvitamin D [25(OH)D] were measured by competitive electrochemiluminescence immunoassay. Results: In total, 338 children (188 boys, 150 girls) with mean age of 3.31 years were enrolled. The percentages of children with deficient, insufficient, and sufficient levels of 25(OH)D were 40.24%, 25.44%, and 34.32%, respectively. Clinical signs of VDD were seen in only 8.53% of the children. The mean (±SD) levels of 25(OH)D were 27.48 (15.99) ng/mL. On univariate analysis, deficient levels of 25(OH)D were associated with relatively younger age group, female sex, failure to thrive, exclusive breastfeeding, inadequate sun exposure, and no vitamin D supplements. Conclusion: A high prevalence of clinical and biochemical VDD was noted in apparently healthy children belonging to the USES.

Background: Positive autoantibodies and its association with the clinical course of type 1 diabetes mellitus (T1DM) have been reported worldwide, however, no such data have been reported in United Arab Emirates population. Objectives: To study the prevalence of positive autoantibodies in T1DM pediatric patients and its association with the clinical presentation. Methods: Descriptive retrospective chart review of all new cases of pediatric T1DM at Tawam Hospital. Electronic patient records accessed to obtain data. Results: 61 patients were identified. 88%±8.1 had at least 1 positive antibody and 82% of all patients were positive for anti- glutamic acid decarboxylase (GAD). While comparing the group of any positive antibody (n=54) with the group of all negative antibodies (n=7), a significant difference was found in the mean HbA1C (p=0.02) and nationality (p=0.03). Conclusion: The vast majority of our T1DM pediatric patients are autoantibody positive, and anti-GAD antibodies were the most commonly detected antibodies.

Patients with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency need glucocorticoid (GC) therapy, which alters bone mineral metabolism. We analyze clinical and biochemical parameters and different polymorphisms of candidate genes associated with bone mineral density (BMD) in CAH patients. The CAH patients treated with GC and healthy controls were studied. Anthropometric parameters, biochemical markers of bone turnover, and BMD were evaluated. Polymerase chain reaction technique was used to genotype different candidate genes. The 192-192 genotype frequency ( IGF-I ) was lower in poorly controlled patients than that from controls. In CAH patients, FF genotype (vitamin D receptor, VDR ) correlated with lower lumbar spine BMD and there was a significant association between the 0-0 genotype ( IGF-I ) and high values of β-CrossLaps and a low total BMD. This study contributes to understanding of the association of genetic determinants of BMD with the variable response to GC treatment in CAH patients and demonstrates the usefulness of these genetic polymorphisms.

Objective: To investigate the protective effects of a pentadecapeptide of islet neogenesis-associated protein (INGAP-PP) on transplanted islets function. Methods: Islets were cultured in RPMI 1640 with or without INGAP-PP (10 μg/mL). After 24 h, the viability of the islets and glucose-stimulated insulin secretion (GSIS) were measured. The expression of genes B cell lymphoma/lewkmia2 ( Bcl2 ) and protein kinase B ( Akt ) were detected by RT-PCR assay. Healthy rats transplanted with islets under the renal capsule were injected with INGAP-PP or saline in in the abdominal cavity. One week later, the expression of insulin nestin pancreatic ( nestin ) and duodenal homeobox 1 ( Pdx1 ) and proliferating cell nuclear antigen ( PCNA ) in the transplanted islets were observed by immunohistochemistry. After that they were transplanted to the renal capsule of diabetic rats. Results: 1. The amount of insulin released was increased in co-cultured group in concentration of 16.7 mmol/L glucose, which was (185.00±20.01 μU/mL) vs. (58.67±17.03 μU/mL). Gene expression of Bcl2 (0.61±0.22 vs. 0.50±0.21) and Akt (1.12±0.19 vs. 0.94±0.16) in the co-cultured group were increased compared with that of the control group. Islets viability in the co-cultured group (683.9±7.08) was higher than that of control group (547.9±8.02). The stimulating index (SI) of the co-cultured group was also higher than that of the control group. 2. The group of islets under the renal capsule which were co-cultured and injected with INGAP-PP had the more nestin expression in the islets. Conclusions: The function of islet can be protected by the INGAP-PP, which will promote the viability, differentiation and regeneration of islet before transplantation. And it will be beneficial for the function of allograft after islets transplantation.

Objectives: This study aimed to [1] confirm that nonobese adolescents with polycystic ovary syndrome (PCOS) have higher anti-Mullerian hormone (AMH) than controls; [2] examine the relationship of AMH with PCOS features and hormonal profile; and [3] approximate an AMH value that discriminates between adolescents with PCOS and controls. Design: Case-control study. Setting: Subspecialty ambulatory clinic. Patients: Thirty-one nonobese adolescent girls (age 13–21 years), 15 with PCOS diagnosed using the National Institutes of Health (NIH) criteria and 16 healthy control subjects. Subjects and controls were comparable for body mass index z-score, age and ethnicity. Main outcome measure(s): AMH in PCOS subjects and control groups, correlation of AMH with hormonal parameters. Results: AMH was higher in PCOS subjects (4.4±3.4 ng/mL) than in controls (2.4±1.3 ng/mL), when adjusted for menstrual age. In the entire group (PCOS and controls), AMH correlated with androgens, ovarian size and the presence of polycystic ovary (PCO) appearance. There was no difference in average ovarian size between PCOS (7.1±2.6 cm 3 ) and controls (6.7±1.8 cm 3 ). PCOS subjects were 1.49 times more likely to have AMH >3.4 ng/mL (confidence interval 0.98–2.26 ng/mL). Conclusions: Our data suggest that AMH may be a useful adjunct in the diagnosis of PCOS in adolescents.

Objective: We assessed the association of breast-feeding and timing of solid food introduction with childhood obesity. Methods: The children were grouped according to the duration of breast-feeding (0–1, 2–6, 7–12, 13–18, and 19–24 months) and the age at which solid foods were introduced (<4, 4–5, and ≥6 months). Results: In this study, we enrolled 4990 children aged 2–14 years. The rate of exclusive breast-feeding at 6 months of age was 49.1%. We found no association between the duration of breast-feeding and childhood obesity [odds ratio (OR) 0.948, 95% confidence interval (95% CI) 0.694–1.295]. The regression analysis revealed no significant differences in obesity or overweight rates between the early and late introduction to solid food groups (OR 0.993, 95% CI 0.645–1.531). Conclusions: Although breastfeeding has been previously reported to protect against childhood obesity, we were unable to find a significant association between obesity and either longer duration of breastfeeding or later introduction to solid foods in our sample.

We report a novel NR0B1 mutation in a patient affected with X-linked adrenal hypoplasia congenita (X-AHC). The proband first presented with a generalized convulsion at 11 years, 4 months. His clinical and biochemical presentations were consistent with adrenal insufficiency. His basal 17-hydroxyprogesterone (17-OHP) level was not high, and the poor response in 17-OHP on ACTH stimulation test excluded congenital adrenal hyperplasia. At 14 years of age, he did not show any signs of puberty, with low levels of LH, FSH, and testosterone and unresponsiveness to lutenizing hormone releasing hormone stimulation test. Direct DNA sequencing revealed that the proband is hemizygous for a novel NR0B1 mutation (c.1177_1180delGGCC, p.Gly393Cysfs*4). The mother is the conductor of the mutation, which is likely pathogenic as the C-terminus truncated protein lacks the activation function-2 (AF2-TA) transactivation domain, which is highly conserved among members of the nuclear receptor superfamily.

The aim of this study was to determine reliable cut-off levels of basal gonadotropin and to assess the correlation of obstetric ultrasound parameters with the GnRH stimulation test. The GnRH stimulation test was performed in a cohort of young female patients who presented at our hospital for the evaluation of early signs of puberty. Using receiver operating curves (ROCs), the sensitivity and specificity of basal luteinising hormone (LH), follicle stimulating hormone (FSH), basal and stimulated LH/FSH ratio, oestradiol levels and ultrasonographic parameters were evaluated at each level, and the area under curve (AUC) was measured. One hundred female children were assessed. We found that LH levels, peak LH/FSH ratio, fundal/cervical ratio, uterus length, and ovarian volume were reliable predictors of central precocious puberty (CPP). Cut-off levels of basal LH and the peak LH/FSH ratio had high specificity in our cohort. In addition, obstetric ultrasound parameters represent reliable predictors for the diagnosis of CPP.

Background: Recombinant human growth hormone (rhGH) availability has allowed the treatment of a greater number of growth disorders. It is important to get an insight into the clinical characteristics of the paediatric population before rhGH treatment. Methods: An observational, retrospective and multicentre study was conducted to evaluate the patients’ baseline characteristics prior to rhGH therapy. Results: A total of 1404 patients (53.8% males) aged 0.5–17.3 years were included. Clinical conditions were as follows: GH deficiency (GHD), 66.0%; small for gestational age (SGA), 29.7%; and Turner syndrome (TS), 4.3%. Male gender was predominant in most growth disorders; age at diagnosis was higher in GHD patients; therapy with rhGH started at lower chronological age in SGA and TS groups. Conclusion: The baseline characteristics of the population to be treated with rhGH were similar to those reported in other growth databases. Delayed age at treatment initiation should increase the awareness of these disorders among general paediatricians and entice them to refer children suspected of having these disorders to a specialist.

Introduction: Obesity and hypertension are recognised risk factors for the development of atherosclerosis. It has not been proven whether their co-existence increases the synthesis of pro-inflammatory TNF-α and what the levels of soluble receptors of this cytokine (sTNF-R) are. This study is aimed to investigate whether there exists a relationship between TNF-α and sTNF-R concentrations in blood serum with the occurrence of obesity or obesity combined with primary hypertension in teenagers. Material and method: 68 persons, aged 9–17, including 32 persons with primary obesity (Group I) and 36 with primary obesity combined with primary hypertension (Group II). TNF-α (pg/mL) and sTNF-R (ng/mL) concentrations were determined in serum samples using the ELISA method with sets of reagents manufactured by Bender Med Systems GmbH. Results: No significant differences in TNF-α, sTNF-R, glucose or insulin concentrations were found between Group I and Group II. These concentrations were not correlated with the age and the nutritional status of the patients or with each other in either of the groups. Conclusion: Both obese teenagers and teenagers exhibiting obesity combined with hypertension (as two atherosclerosis risk factors) are characterised by comparable concentrations of TNF-α and its soluble receptors.

Celiac disease (CD) is associated with type 1 diabetes mellitus (T1DM), which is known to be associated with abnormal lipid profiles. We aimed to examine the impact of CD on lipid profiles in persons with T1DM. Subjects with T1DM were identified by database and medical record review. Patients were classified as T1DM+CD or T1DM based on CD antibody and endoscopy results. The most recent (before age 20 years) non-fasting lipid panel (NFLP) prior to CD diagnosis for T1DM+CD subjects was compared to the most recent NFLP for T1DM subjects. Adjusted analysis showed T1DM+CD had lower HDL compared with T1DM (T1DM+CD 51.4 mg/dL, T1DM 62.2 mg/dL, p=0.017). There were no other differences in NFLP. In our sample, patients with T1DM+CD had lower HDL levels. Considering the increased cardiovascular disease risk of patients with T1DM, those who also have CD may be at even greater risk due to the association with lower HDL.

Hereditary vitamin D-resistant rickets (HVDRR) is an autosomal recessive disorder characterized by end-organ resistance to 1α,25-dihydroxyvitamin D3 (1,25D3). Clinically, the syndrome is recognized by severe early onset rickets with bowing of the lower extremities, short stature, and often alopecia. Here, we report a case series on three siblings who had HVDRR with varied clinical findings.

Persistent Müllerian duct syndrome (PMDS) is an autosomal recessive disorder of sex development (DSD) characterized by the presence of Müllerian duct derivatives in 46, XY phenotypic males. To date, more than 50 different mutations of the anti-Müllerian hormone gene ( AMH ) have been reported. Here, we report two novel mutations of AMH in a Japanese patient with PMDS. A 1-year-old male presented with bilateral cryptorchidism and normal male external genitalia. A laparoscopic surgery revealed a uterus and fallopian tubes. Serum AMH was very low. The patient’s elder brother was also diagnosed as having PMDS at another hospital. Genetic analysis of AMH showed two novel mutations of p.N486T and p.V527L. Given that these two amino acids are well conserved among different species of AMH, the substitution of two amino acids might affect the normal function of AMH. In conclusion, PMDS should be included in differential diagnoses of cryptorchidism.

Objective: This report describes two adolescent males in China who suffered from type 2 diabetes mellitus (T2DM) and hyperglycemic hyperosmolar syndrome (HHS) complicated by rhabdomyolysis (RM). After sufficient fluid administration, both patients recovered. Design: Case report. Results: These two obese patients suffered from T2DM, DKA and HHS. Because of insufficient fluid administration, these patients became aggravated and suffered from RM. After aggressive fluid resuscitation and insulin injection, the conditions of the two patients improved. Insulin administration was ceased after approximately 1 month of subcutaneous injections. The two patients attained good glucose control with diet management. Conclusions: HHS is one of the most severe complications of T2DM. RM is a sign that the condition of a patient with HHS may worsen. Although management strategies are undefined, effective fluid infusion was shown to be helpful. Thus, the early signs of HHS and RM should be recognized so as to avoid severe complications.

Acquired hypothyroidism secondary to iodine deficiency is rarely reported in iodine-replete environments. The case of a 9-year-old patient with severe acquired hypothyroidism due to iodine deficiency is presented. His deficiency occurred because of a restrictive diet used to control eosinophilic esophagitis. Hypothyroidism and iodine deficiency were quickly corrected with a kelp supplement.

Donohue syndrome (DS) is a severe form of congenital insulin resistance due to mutation(s) in the insulin receptor ( INSR ) gene. Given the similarities between insulin and insulin-like growth factor 1 (IGF-1) receptors, recombinant human IGF-1 (rhIGF-1) has been used to treat severe insulin resistance due to INSR mutation(s). Traditional subcutaneous therapy may be limited by the shortened IGF-1 half-life in these patients. We report the case of a female with molecularly confirmed DS treated with continuous rhIGF-1 therapy via an insulin pump. With treatment, the patient’s hemoglobin A1c decreased from 9.8% to 8.8%, and her weight increased by 0.8 kg. Development of an ovarian tumor complicated her course, but it was unclear whether this was related to rhIGF-1 therapy. Limited treatment options exist for patients with DS. The use of continuous rhIGF-1 via an insulin pump may be a viable option, although further experience is needed to establish safety and efficacy.

Diabetic ketoacidosis (DKA) accompanies any other intra-abdominal pathology. Serum amylase/lipase levels are commonly used in order to rule out acute pancreatitis in patients having abdominal pain in DKA. A more specific and noninvasive diagnostic tool – amylase/creatinine clearance ratio (ACCR) – can be used to rule out pancreatitis in patients with DKA. A 14-year-old girl was admitted with abdominal pain and nausea. She had been followed up for type 1 diabetes mellitus for the last 5 years. The serum amylase levels were increased up to 687 U/L (normal: 28–120 U/L) on the third day of hospitalization. Simultaneous serum and urinary amylase concentrations were measured, and ACCR was calculated (1.2%). The diagnosis of pancreatitis was ruled out. The serum amylase levels decreased in the following days, and she was discharged. ACCR determination is a simple and specific test to diagnose pancreatitis, especially in patients with DKA.

We report a case of a 17-year-old girl with a history of congenital human immunodeficiency virus (HIV) infection and lipodystrophy secondary to highly active antiretroviral therapy (HAART). She developed severe worsening of preexisting hypertriglyceridemia after treatment with oral contraceptive pills (OCP) for polycystic ovary syndrome. Her hypertriglyceridemia improved upon OCP discontinuation. Although it is known that estrogen combined with progestins have a negative effect on triglycerides and high-density lipoprotein (HDL) cholesterol levels, to our knowledge the association of HAART-related lipodystrophy and severe hypertriglyceridemia after OCP use has not been reported in the literature. We recommend avoiding the use of OCPs in patients with lipodystrophy due to the increased risk of worsening hypertriglyceridemia.

Congenital hyperinsulinism is the most frequent cause of persistent hypoglycemia in infancy. We present the case of a preterm, large-for-gestation-age infant with congenital hyperinsulinism who was found to have a novel p.Q392H homozygous mutation in the ABCC8 gene. The patient had severe brain damage, despite early diagnosis and appropriate management. The new mutations may provide an understanding of the prognosis and treatment of the disease. In addition, the data will help the family make informed decisions about future pregnancies.

Autoimmune polyglandular syndrome type 1 (APS-1), also referred to as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), is a rare autoimmune disease that results from autosomal recessive mutations of the human autoimmune regulatory (AIRE) gene. We present the case of a 17-year-old North American girl of primarily Norwegian descent with a novel AIRE gene mutation causing APS-1. In addition to the classic triad of chronic candidiasis, hypoparathyoidism and autoimmune adrenocortical insufficiency, she also has vitiligo, intestinal malabsorption, autoimmune hepatitis, autoimmune hypothyroidism, myositis, myalgias, chronic fatigue, and failure to thrive. Genetic testing revealed heterozygosity for c.20_115de196 and c.967_979del13 mutations in the AIRE gene. The AIRE gene c.20_115de196 mutation has not been previously reported.

We present two cases of transient central diabetes insipidus in preterm neonates with post-hemorrhagic hydrocephalus. Although the association between intraventricular hemorrhage and diabetes insipidus has been described in preterm infants, the association between diabetes insipidus and hydrocephalus, and the fact that such central diabetes insipidus could be reversible with the reduction of ventricular size, either because of spontaneous resolution or the placement of ventriculo-peritoneal shunt is first described here in neonates.

Pompe disease is an autosomal recessive lysosomal glycogen storage disorder (GSD) caused by acid α-glucosidase (GAA) deficiency. Pompe disease has a broad genotypic and phenotypic spectrum. The infantile-onset form is the most severe form and presents with hypotonia and cardiomyopathy in early infancy. The probands who died were found to have GSD type II based on clinical and biochemical findings. We report two families with Pompe disease in whom the parents’ molecular analysis revealed two novel mutations: c.2045A>G (p.Q682R) and c.763C>T (p.Q255X).