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Aims: High-density lipoprotein (HDL) function may be altered in patients with chronic disease, transforming the particle from a beneficial vasoprotective molecule to a noxious pro-inflammatory equivalent. Adolescents with Type 1 diabetes often have elevated HDL, but its vasoprotective properties and relationship to endothelial function have not been assessed., Methods and Results: Seventy adolescents with Type 1 diabetes (age 10-17 years) and 30 age-matched healthy controls supplied urine samples for the measurement of early renal dysfunction (albumin:creatinine ratio; ACR), blood samples for the assessment of cardiovascular risk factors (lipid profiles, HDL functionality, glycaemic control, and inflammatory risk score), and had their conduit artery endothelial function tested using flow-mediated dilation (FMD). HDL-c levels (1.69 ± 0.41 vs. 1.44 ± 0.29mmol/L; P < 0.001), and glycated haemoglobin (HbA1c) (8.4 ± 1.2 vs. 5.4 ± 0.2%; P < 0.001) were increased in all patients compared with controls. However, increased inflammation and HDL dysfunction were evident only in patients who also had evidence of early renal dysfunction (mean ± standard deviation for high-ACR vs. low-ACR and healthy controls: inflammatory risk score 11.3 ± 2.5 vs. 9.5 ± 2.4 and 9.2 ± 2.4, P < 0.01; HDL-mediated nitric-oxide bioavailability 38.0 ± 8.9 vs. 33.3 ± 7.3 and 25.0 ± 7.7%, P < 0.001; HDL-mediated superoxide production 3.71 ± 3.57 vs. 2.11 ± 3.49 and 1.91 ± 2.47nmol O2 per 250 000 cells, P < 0.05). Endothelial function (FMD) was impaired only in those who had both a high inflammatory risk score and high levels of HDL-c (P < 0.05)., Conclusion: Increased levels of HDL-c commonly observed in individuals with Type 1 diabetes may be detrimental to endothelial function when accompanied by renal dysfunction and chronic inflammation., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Context: Retrospective studies suggest that adolescents with craniopharyngioma and hypothalamic obesity have increased sleep-disordered breathing (SDB)., Objectives: The objectives of this study were to compare the prevalence of SDB in adolescents with craniopharyngioma-related obesity compared with body mass index (BMI)-matched controls and to explore possible relationships between SDB, insulin resistance, and adipocytokines., Design: This was a cross-sectional study of obese craniopharyngioma and obese control adolescents., Setting: Subjects were evaluated in the clinical investigation unit at the Hospital for Sick Children, Toronto., Patients: Fifteen patients with craniopharyngioma-related obesity and 15 BMI-matched controls were recruited and tested., Interventions: Each subject underwent fasting blood work, frequent sampled iv glucose tolerance test, polysomnography, and abdominal magnetic resonance imaging with calculation of visceral and sc adipose tissue., Main Outcome Measures: Main measures included insulin sensitivity, sleep efficiency, and fragmentation., Results: Insulin sensitivity was lower in craniopharyngioma subjects compared with control subjects (0.96 +/- 0.34 vs. 1.67 +/- 0.7, P = 0.01). Sleep-onset latency (19.3 +/- 27.8 vs. 31.9 +/- 23.4, P = 0.03) and oxygen saturations (rapid eye movement sleep: 89.0 +/- 5.1 vs. 94.2 +/- 2.3, P < 0.001; non-rapid eye movement sleep: 88.4 +/- 5.6 vs. 94.3 +/- 1.5, P < 0.001) were lower in craniopharyngioma. Obstructive apnea-hypopnea index (OAHI) (7.5 +/- 9.0 vs. 1.5 +/- 1.5, P = 0.03) was higher in craniopharyngioma. Respiratory distress index and OAHI correlated negatively with adiponectin concentrations (r = -0.61, P = 0.03, r = -0.71, P = 0.006, respectively) in craniopharyngioma. On multiple regression, TNF-alpha and craniopharyngioma were independent positive predictors of sleep-onset latency and adiponectin and craniopharyngioma were significant predictors (negative and positive, respectively) of OAHI., Conclusions: SDB is increased in adolescents with craniopharyngioma-related obesity compared with BMI-matched controls. Routine polysomnography should be considered in obese patients with craniopharyngioma and appropriate treatment initiated.

Background: Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is one of the most common autosomal recessive disorders. Many issues in the management of CAH in children still remain unresolved., Objective: To assess how children with CAH are treated in Canada., Methods: Fifty-nine paediatric endocrinologists and postgraduate trainees from across Canada took part in a survey that evaluated four areas of CAH management: type and dose of glucocorticoid therapy, current use of alternative therapies, monitoring of care, and approach/attitude to prenatal diagnosis and treatment of CAH., Results and Conclusions: The present survey demonstrated that there is general agreement among paediatric endocrinologists in Canada regarding the management of patients with CAH, which includes very little use of newer antiandrogen therapies. The goal remains to be the optimization of currently available therapy to ensure normal growth and sexual maturation without any evidence of glucocorticoid excess or deficiency. Prenatal diagnosis and management is widely, but infrequently, used.

We examined the patterns of TSH, T(4), and treatment schedules from diagnosis to 4 yr of age in 125 children (50 males anf 75 females) with congenital hypothyroidism (CH). Subjects were divided into 3 groups based on their thyroid scans: 1) athyreosis (n = 31), 2) dysgenesis (n = 54; 49 lingual and 5 hypoplastic), and 3) dyshormonogenesis (n = 40). Follow-up evaluation was carried out at 2-4 wk and 3, 6, 9, 12, 24, 36, and 48 months of age. Median gestational age, age at onset of therapy, and starting L-T(4) dose were similar in the three groups. In infants with athyreosis median screening TSH levels were higher (P < 0.02) and confirmatory T(4) levels were lower than in the other two groups (P < 0.01 vs. dysgenetic; P < 0.05 vs. dyshormonogenetic CH). During the first 6 months of therapy, mean TSH levels were highest in the athyrotic group, intermediate in the dysgenetic group, and lowest in the dyshormonogenetic group. In children with athyreosis, TSH levels normalized by 12 months of age. At 12 months dysgenetic patients had the highest TSH levels (P < 0.05). During the entire study period, TSH levels were lowest in patients with dyshormonogenesis (except at 48 months) and normalized earlier. Mean T(4) levels normalized by 2-4 weeks in all groups. At 3 and 6 months, the percentage of patients who required dose changes was highest in the athyrotic group, and at 12 months it was highest in the dysgenetic group. The athyrotic group received the highest dose of L-T(4), and dyshormonogenetic group received the lowest dose. We conclude that treatment and follow-up schedules for CH may differ in the three etiological categories based on the different hormonal patterns and responses to therapy. Children with athyreosis need close monitoring particularly early in life, whereas those with dysgenesis and dyshormonogenesis require more attention later in life.

Infants and toddlers comprise a small minority of individuals with type 1 diabetes. However, epidemiological data provide evidence of a trend towards diagnosis at a younger age. These very young children pose significant challenges to both the health care professionals involved in their care as well as to their families. At diagnosis, younger children often do not present with classical symptoms of diabetes. Unless health professionals remain alert to the possibility of diabetes being the underlying cause of a child's illness, the diagnosis may be missed. Once the diabetes has been diagnosed, the major challenge is to set up a treatment regimen that is both reasonable and realistic; in the youngest children, the goal of very tight metabolic control may expose them to episodes of severe hypoglycemia which may lead to subtle cognitive impairments later in life. The therapeutic regimen must balance the naturally erratic eating and exercise patterns of very young children with the need to maintain adequate metabolic control. Setting a blood glucose target range of 6 to 12 mmol/L usually allows this to be accomplished. Diabetes during early childhood creates a psychosocial challenge to the families of these children. Successful management of infants and toddlers with diabetes depends on a well functioning and educated family, the availability of diabetes health care team experienced in the treatment of these youngsters, and the involvement of the extended family, child care personnel and others who play a role in their daily care.

Apparent mineralocorticoid excess (AME) is a genetic disorder causing pre- and postnatal growth failure, juvenile hypertension, hypokalemic metabolic alkalosis, and hyporeninemic hypoaldosteronism due to a deficiency of 11 beta-hydroxysteroid dehydrogenase type 2 enzyme activity (11 beta HSD2). The 11 beta HSD2 enzyme is responsible for the conversion of cortisol to the inactive metabolite cortisone and therefore protects the mineralocorticoid receptors from cortisol intoxication. Several homozygous mutations are associated with this potentially fatal disease. We have examined the phenotype, biochemical features, and genotype of 14 patients with AME. All of the patients had characteristic signs of a severe 11 beta HSD2 defect. Birth weights were significantly lower than those of their unaffected sibs. The patients were short, underweight, and hypertensive for age. Variable damage of one or more organs (kidneys, retina, heart, and central nervous system) was found in all of the patients except one. The follow-up studies of end-organ damage after 2-13 yr of treatment in six patients demonstrated significant improvement in all patients. The urinary metabolites of cortisol demonstrated an abnormal ratio with predominance of cortisol metabolites, i.e. tetrahydrocortisol plus 5 alpha-tetrahydrocortisol/tetrahydrocortisone was 6.7-33, whereas the normal ratio is 1.0. Infusion of [11-3H]cortisol resulted in little release of tritiated water, indicating the failure of the conversion of cortisol to cortisone. Thirteen mutations in the HSD11B2 gene have been previously published, and we report three new genetic mutations in two patients, one of whom was previously unreported. All of the patients had homozygous defects except one, who was a compound heterozygote. Our first case had one of the most severe mutations, resulting in the truncation of the enzyme 11 beta HSD2, and died at the age of 16 yr while receiving treatment. Three patients with identical homozygous mutations from different families had varying degrees of severity of clinical and biochemical features. Due to the small number of patients with identical mutations, it is difficult to correlate genotype with phenotype. In some cases, early and vigilant treatment of AME patients may prevent or improve the morbidity and mortality of end-organ damage such as renal or cardiovascular damage and retinopathy. The outcome of treatment in more patients may establish the efficacy of treatment.

Mutations in the gene encoding human thyroid hormone receptor beta (hTR beta) have been associated with generalized resistance to thyroid hormone (GRTH). This disorder is associated with significant behavioral abnormalities. We examined the hTR beta gene in a family with members who manifest inappropriately normal TSH, elevated free T4, and free and total T3. Sequence analysis showed a cytosine to thymine transition at nucleotide 1642 in one allele of the index patient's genomic DNA. This altered proline to serine at codon 453. The resulting mutant receptor when expressed in vitro bound DNA with high affinity, but the T3 affinity of the receptor was impaired. The mutant TR demonstrated a dominant negative effect when cotransfected with two isoforms of wild-type receptor and also in the presence of TR variant alpha 2 in COS-1 cells. Mutations of codon 453 occur more frequently than at other sites, and four different amino acid substitutions have been reported. Significant differences in phenotype occur among affected individuals, varying from normality to moderately severe GRTH. There is no clear correlation between Ka or in vitro function of the mutant receptor, and phenotype. This study extends the association between GRTH and illness, and indicates that early diagnosis and counseling are needed in families with TR beta 1 abnormalities.

An automated "high-pressure" liquid-chromatographic assay for hemoglobin A1c is described. We use a 45-min incubation in acetate buffer (pH 5.5) to eliminate labile glycated hemoglobins. In this automated system conventional modules are used but it incorporates a solvent-switching valve to select either of two buffers, which differ in pH and NaCl concentration. The chromatographic column contains "polyCAT" (a weak cation-exchanger, polyaspartic acid linked to silica). Run time is 14 min per sample. The method is precise and results correlate well with those by other ion-exchange procedures.