Louise S. Conwell

Early Adolescent Smoking and a Web of Personal and Social Disadvantage

Objective:  To examine concurrent physical, educational, behavioural, social and family factors associated with cigarette smoking in adolescents at 14 years.

Neonatal complete generalized glucocorticoid resistance and growth hormone deficiency caused by a novel homozygous mutation in Helix 12 of the ligand binding domain of the glucocorticoid receptor gene (NR3C1).

CONTEXT Glucocorticoid resistance is a rare genetic condition characterized by reduced sensitivity to cortisol signaling and subsequent hyperactivation of the hypothalamic-pituitary-adrenal axis. OBJECTIVE The objective was to confirm the diagnosis of glucocorticoid resistance in the patient, to determine the degree of suppression of cortisol and ACTH levels in response to dexamethasone, and to determine the underlying genetic abnormality and functional consequences of the mutation. PATIENT AND METHODS The patient presented on the first day of life with profound hypoglycemia. Initial cortisol levels were appropriately elevated; however, the patient was found to have persistently elevated levels of both cortisol and ACTH. The baby developed a tanned appearance and severe hypertension and fatigued easily with feeding. Serial oral dexamethasone suppression tests were performed with doses escalating from 0.125 mg to 12 mg dexamethasone given at 2300 h. Sequencing of the glucocorticoid receptor gene was performed along with functional studies of the glucocorticoid receptor. GH secretion was assessed with an arginine glucagon stimulation test. RESULTS Cortisol and ACTH levels did not suppress with doses of up to 12 mg dexamethasone. A 2-bp deletion was found at amino acid position 773 of the glucocorticoid receptor ligand binding domain. A complete lack of dexamethasone binding and in vitro biological effect was demonstrated. GH stimulation testing was consistent with GH deficiency. CONCLUSION The homozygous mutation in the ligand-binding domain of the glucocorticoid receptor gene resulted in a functionally inactive glucocorticoid receptor and apparent complete glucocorticoid resistance with biochemical GH deficiency.

Hypothalamic Obesity following Craniopharyngioma Surgery: Results of a Pilot Trial of Combined Diazoxide and Metformin Therapy

Objective. To assess the effect of combined diazoxide-metformin therapy in obese adolescents treated for craniopharyngioma. Design. A prospective open-label 6-month pilot treatment trial in 9 obese subjects with craniopharyngioma. Diazoxide (2 mg/kg divided b.i.d., maximum 200 mg/day) and metformin (1000 mg b.i.d.). Whole body insulin sensitivity index (WBISI) and area-under-the-curve insulin (AUCins) were calculated. Results. Seven subjects completed: 4M/3F, mean ± SD age years, weight  kg, BMI  kg/m2, and BMI SDS . Two were withdrawn due to vomiting and peripheral edema. Of participants completing the study, the mean ± SD weight gain, BMI, and BMI SDS during the 6 months were reduced compared to the 6 months prestudy ( versus  kg, ; versus  kg/m2, ; versus , , resp.). AUCins correlated with weight loss (, ) and BMI decrease (, ). Conclusion. Combined diazoxide-metformin therapy was associated with reduced weight gain in patients with hypothalamic obesity. AUCins at study commencement predicted effectiveness of the treatment.

Dermatological Complications of Continuous Subcutaneous Insulin Infusion in Children and Adolescents

OBJECTIVES To describe the dermatological changes associated with continuous subcutaneous insulin infusion (CSII) therapy in youth with type 1 diabetes mellitus (T1D). To assess their association with duration of CSII, age, adiposity, HbA1(c), insulin dose, insulin brand, infusion set or site. STUDY DESIGN We conducted a cross-sectional study of 50 consecutive patients with T1D who were using CSII for >6 months (26 female; age, 13.3 +/- 3.5 years [mean +/- SD]; CSII duration, 2.8 +/- 1.7 years; HbA1(c), 7.7% +/- 1.1%). A grading scale was devised. Ultrasound scanning was performed in 8 subjects. RESULTS The mean (+/-SD) severity score was 6.3 +/- 3.5 (range, 0-14; maximum possible, 69). Most common were scars <3 mm diameter (94%), erythema not associated with nodules (66%), subcutaneous nodules (62%), and lipohypertrophy (42%). There was a significant negative correlation between severity score and body mass index z-score (r = -0.3, P = .039), but no correlation with HbA1(c), insulin brand or site. Infusion sets inserted at 90 degrees were associated with lower scores (P = .03). Less than 5% of patients and parents considered stopping CSII because of skin concerns. Ultrasound scanning results of CSII sites revealed mild increased echogenicity of the dermis and hypodermis. CONCLUSIONS Dermatological changes were frequent, with increased severity associated with lower adiposity. These complications were not associated with glycemic control, nor did they prompt most to consider stopping CSII.

Serum vitamin D levels are lower in Australian children and adolescents with type 1 diabetes than in children without diabetes

Vitamin D is synthesised in the skin through the action of UVB radiation (sunlight), and 25‐hydroxy vitamin D (25OHD) measured in serum as a marker of vitamin D status. Several studies, mostly conducted in high latitudes, have shown an association between type 1 diabetes mellitus (T1DM) and low serum 25OHD. We conducted a case–control study to determine whether, in a sub‐tropical environment with abundant sunlight (latitude 27.5°S), children with T1DM have lower serum vitamin D than children without diabetes. Fifty‐six children with T1DM (14 newly diagnosed) and 46 unrelated control children participated in the study. Serum 25OHD, 1,25‐dihydroxy vitamin D (1,25(OH)2D) and selected biochemical indices were measured. Vitamin D receptor (VDR) polymorphisms Taq1, Fok1, and Apa1 were genotyped. Fitzpatrick skin classification, self‐reported daily hours of outdoor exposure, and mean UV index over the 35 d prior to blood collection were recorded. Serum 25OHD was lower in children with T1DM (n = 56) than in controls (n = 46) [mean (95%CI) = 78.7 (71.8–85.6) nmol/L vs. 91.4 (83.5–98.7) nmol/L, p = 0.02]. T1DM children had lower self‐reported outdoor exposure and mean UV exposure, but no significant difference in distribution of VDR polymorphisms. 25OHD remained lower in children with T1DM after covariate adjustment. Children newly diagnosed with T1DM had lower 1,25(OH)2D [median (IQR) = 89 (68–122) pmol/L] than controls [121 (108–159) pmol/L, p = 0.03], or children with established diabetes [137 (113–153) pmol/L, p = 0.01]. Children with T1DM have lower 25OHD than controls, even in an environment of abundant sunlight. Whether low vitamin D is a risk factor or consequence of T1DM is unknown.

Considering statins for cholesterol-reduction in children if lifestyle and diet changes do not improve their health: A review of the risks and benefits

Children who appear healthy, even if they have one or more recognized cardiovascular risk factors, do not generally have outcomes of cardiovascular or other vascular disease during childhood. Historically, pediatric medicine has not aggressively screened for or treated cardiovascular risk factors in otherwise healthy children. However, studies such as the P-Day Study (Pathobiological Determinants of Atherosclerosis in Youth), and the Bogalusa Heart Study, indicate that healthy children at remarkably young ages can have evidence of significant atherosclerosis. With the increasing prevalence of pediatric obesity, can we expect more health problems related to the consequences of pediatric dyslipidemia, hypertriglyceridemia, and atherosclerosis in the future? For many years, medications have been available and used in adult populations to treat dyslipidemia. In recent years, reports of short-term safety of some of these medications in children have been published. However, none of these studies have detailed long-term follow-up, and therefore none have described potential late side-effects of early cholesterol-lowering therapy, or potential benefits in terms of reduction of or delay in cardiovascular or other vascular end-points. In 2007, the American Heart Association published a scientific statement on the use of cholesterol-lowering therapy in pediatric patients. In this review paper, we discuss some of the current literature on cholesterol-lowering therapy in children, including the statins that are currently available for use in children, and some of the cautions with using these and other cholesterol-lowering medications. A central tenet of this review is that medications are not a substitute for dietary and lifestyle interventions, and that even in children on cholesterol-lowering medications, physicians should take every opportunity to encourage children and their parents to make healthy diet and lifestyle choices.

Relation of reduced preclinical left ventricular diastolic function and cardiac remodeling in overweight youth to insulin resistance and inflammation

Insulin resistance (IR) and inflammation are associated with an increased risk of cardiovascular disease and may contribute to obesity cardiomyopathy. The earliest sign of obesity cardiomyopathy is impaired left ventricular (LV) diastolic function, which may be evident in obese children and adolescents. However, the precise metabolic basis of the impaired LV diastolic function remains unknown. The aims of this study were to evaluate cardiac structure and LV diastolic function by tissue Doppler imaging in overweight and obese (OW) youth and to assess the relative individual contributions of adiposity, IR, and inflammation to alterations in cardiac structure and function. We studied 35 OW (body mass index standard deviation score 2.0±0.8; non-IR n=19, IR n=16) and 34 non-OW youth (body mass index standard deviation score 0.1±0.7). LV diastolic function was reduced in OW youth compared with non-OW controls, as indicated by lower peak myocardial relaxation velocities (p<0.001) and greater filling pressures (p<0.001). OW youth also had greater LV mass index (p<0.001), left atrial volume index, and LV interventricular septal thickness (LV-IVS; both p=0.02). IR-OW youth had the highest LV filling pressures, LV-IVS, and relative wall thickness (all p<0.05). Homeostasis model of assessment-insulin resistance and C-reactive protein were negative determinants of peak myocardial relaxation velocity and positive predictors of filling pressure. Adiponectin was a negative determinant of LV-IVS, independent of obesity. In conclusion, OW youth with IR and inflammation are more likely to have adverse changes to cardiovascular structure and function which may predispose to premature cardiovascular disease in adulthood.

Reversible cardiomyopathy in paediatric Addison's disease--a cautionary tale.

A 13 year-old girl with clinical features of Addisons disease developed acute cardiac failure after initiation of treatment and after initial clinical improvement. Large doses of i.v. hydrocortisone and oral fludrocortisone, in addition to inotropic and ventilatory support, were required to achieve cardiovascular stability. The cardiomyopathy improved over one week and her condition then remained stable on oral glucocorticoid and mineralocorticoid replacement therapy. Reversible cardiomyopathy is a rare and potentially life-threatening complication of Addisons disease. The second reported paediatric patient is presented, the only one reported to require ventilatory support.

The feasibility of a home-based moderate-intensity physical activity intervention in obese children and adolescents.

Objectives To explore the feasibility of conducting a 10-week home-based physical activity (PA) programme and evaluate the changes in insulin sensitivity (SI) commensurate with the programme in obese young people. Design Open-labelled intervention. Setting Home-based intervention with clinical assessments at a tertiary paediatric hospital. Subjects 18 obese (body mass index (BMI)>International Obesity Task Force age and sex-specific cut-offs) children and adolescents (8–18 years, 11 girls/7 boys) were recruited. 15 participants (nine girls/six boys, mean±SE age 11.8±0.6 years, BMI-SD scores (BMI-SDS) 3.5±0.1, six prepubertal/nine pubertal) completed the intervention. Intervention The programme comprised biweekly home visits over 10 weeks with personalised plans implemented aiming to increase moderate-intensity PA. Pedometers and PA diaries were used as self-monitoring tools. The goals were to (1) teach participants behavioural skills related to adopting and maintaining an active lifestyle and (2) increase daily participation in PA. Outcome measures Mean steps/day were assessed. SI assessed by the frequently sampled intravenous glucose tolerance test and other components of the insulin resistance syndrome were measured. Results Mean steps/day increased significantly from 10 363±927 (baseline) to 13 013±1131 (week 10) (p<0.05). SI was also significantly increased, despite no change in BMI-SDS, and remained so after an additional 10-week follow-up. Conclusions The results suggest that such a home-based PA programme is feasible. SI improved without changes in BMI-SDS. More rigorous evaluations of such programmes are warranted.

Aberrant cervical thymus mimicking a cervical mass

Abstract:  A case of a 9‐year‐old female with suprasternal extension of the thymus mimicking thyroid gland enlargement is described. Ultrasonography successfully established the diagnosis. Aberrant cervical thymic tissue is an infrequently reported cause of paediatric neck masses. It is important to be aware of this entity to prevent anxiety and inappropriate investigation and/or intervention.