Citation for published version (APA): Megson, I. L., Treweeke, A. T., Shaw, A., MacRury, S. M., Setford, S., Frias, J. P., & Anhalt, H. (2015). Continuous Subcutaneous Insulin Infusion in Patients With Type 2 Diabetes: A Cohort Study to Establish the Relationship Between Glucose Control and Plasma Oxidized Low Density Lipoprotein. Journal of Diabetes Science and Technology, 9(3), 573-580. https://doi.org/10.1177/1932296815570359

Context: Mutations in the gene encoding steroidogenic acute regulatory protein (StAR) are the most common cause of lipoid congenital adrenal hyperplasia (lipoid CAH), a disorder characterized by adrenal insufficiency and deficient gonadal steroid synthesis, resulting in female external genitalia in both genetic sexes.Objective: We describe three new cases of lipoid CAH caused by novel mutations in the StAR gene.Patients: An XY subject of Yemeni descent presented with adrenal insufficiency and severe undervirilization. Magnetic resonance imaging (MRI) of the brain showed enlarged subarachnoid spaces consistent with frontal and temporal atrophy. Two XX siblings of Palestinian descent presented with neonatal adrenal insufficiency. One had a borderline intelligence quotient and features of attention deficit hyperactivity disorder. MRI showed areas of supratentorial white matter lesions. In her sister, MRI revealed a Chiari-I malformation.Results: The XY subject was found to have a missense mutation (R182C). Both XX siblings had a dinucleotide deletion at nucleotides 327 - 328 that induces a frame shift that truncates the StAR protein after 68 amino acids.Conclusions: These cases broaden the spectrum of known StAR mutations and suggest that disorders of central nervous system development may arise because of StAR deficiency and/or the metabolic consequences of neonatal adrenal deficiency.

BACKGROUND Obesity and insulin resistance are increasingly common problems in children. Tumor necrosis factor-alpha (TNF-alpha) has important effects on lipid and glucose metabolism. This effect may be mediated through soluble TNF-alpha receptor 2 (sTNFR2). OBJECTIVE To investigate the relationship between insulin resistance and the TNF-alpha system in childhood obesity. CHILDREN AND METHODS Twenty-one obese and six non-obese children were studied. Body mass index (BMI) z-scores, percent body fat (PBF) and waist to hip ratio (WHR) were determined. Fasting serum levels of total cholesterol, HDL-cholesterol, LDL-cholesterol, TNF-alpha and sTNFR2 were measured. A standard 2-hour oral glucose tolerance test (dose of glucose: 1.75 g/kg, max. 75 g) was done. Insulin resistance (IR) was estimated by fasting plasma insulin, plasma insulin at 120 min, homeostasis model assessment (HOMA) and insulin area under the curve (AUC) from OGTT. Insulin sensitivity was estimated by oral glucose insulin sensitivity (OGIS120). RESULTS Among the obese participants, one child (5.2%) was found to have diabetes mellitus and four others (21.1%) impaired glucose tolerance (IGT). Obese children had significantly elevated sTNFR2 levels. Furthermore, the group of obese children with IGT and the patient with newly diagnosed diabetes mellitus together (n = 5) had significantly higher levels of serum sTNFR2 (2,865+/-320 pg/ml) than the rest of the obese (2,460+/-352 pg/ml; p = 0.016) or lean (1,969+/-362 pg/ml; p = 0.014) children. Serum sTNFR2 levels correlated positively with insulin AUC, HOMA IR, fasting plasma insulin, plasma insulin at 120 min, total cholesterol and LDL/ HDL ratio, and negatively with OGIS120. Multiple regression analysis revealed that age, WHR, sTNFR2 and LDL predicted 81% of the variability in glucose at 120 min. CONCLUSION sTNFR2 is a candidate marker of insulin resistance and glucose intolerance.

Graves' disease in pregnancy is a rare condition that directly affects neonatal thyroid function. We describe three newborns born to mothers with Graves' disease and discuss differences in outcomes and management. The first infant presented with a goiter at birth but was euthyroid and did not require therapy. The second infant presented with thyroid storm and the third infant present with neonatal hyperthyroidism, and both required treatment with antithyroid drugs. There was documented elevation of maternal and infant thyroid stimulating hormone immunoglobulin (TSI) levels in all three infants. Management of an infant born to a mother with Graves' disease should include monitoring of both maternal and neonatal thyroid function, and maternal TSI levels during pregnancy. Treatment may be needed if the newborn is symptomatic. With clearance of maternal antibodies and antithyroid drugs, manifestations of abnormal thyroid function in the neonate gradually regress, including eventual resolution of a goiter, if initially present.

Introduction: Nonalcoholic fatty infiltration of the liver is a known sequel of obesity in adults. It has previously been reported that fatty infiltration of the liver affects 2.6% of children and 10–25% adolescents with obesity. Serum levels of alanine (ALT) and aspartate aminotransferase (AST) have been proposed as surrogate markers of hepatic fat accumulation. We describe the incidence of abnormal liver enzymes in obese children involved in Kids–Weight Down Program and attempt to seek correlations between other variables associated with insulin resistance. Methods: One hundred fifty six (ages 5 to 20 years) obese children were enrolled. Liver enzymes, fasting lipid profile, thyroid function tests, glucose and insulin levels were obtained and screened. Results: ALT and AST were elevated in 30/156 (19.2 %) children with obesity and normal glucose tolerance. In the group with elevated liver enzymes, HDL was significantly lower and triglycerides (TG) were significantly higher (P <0.001). TG level correlated positively with ALT level (r=0.39, P< 0.001). While HDL negatively correlated with ALT level (r= − 0.29, p <0.001). Ratio TG/HDL correlated with ALT (r= 0.37, p <0.001) and AST (r=0.27, p< 0.001). Frequency of elevated liver transaminases increases with age: from 15% at 5–10 years of age, to 18 % at 11 to 15 years and 31 % at 16-to 20 years of age. There were no differences in insulin resistance index (QUICKI), BMI or age between groups. Conclusion: Elevated liver transaminases are a frequent complication of obesity in up to 19 % of our patients. Frequency of such complications increases with age. Elevated TG/HDL index can be a marker of abnormal liver enzymes, an important surrogate marker of fatty infiltration of the liver.