Exploring diazoxide and continuous glucose monitoring as treatment for Glut1 deficiency syndrome.

Glut1 deficiency syndrome is caused by SLC2A1 mutations on chromosome 1p34.2 that impairs glucose transport across the blood-brain barrier resulting in hypoglycorrhachia and decreased fuel for brain metabolism. Neuroglycopenia causes a drug-resistant metabolic epilepsy due to energy deficiency. Standard treatment for Glut1 deficiency syndrome is the ketogenic diet that decreases the demand for brain glucose by supplying ketones as alternative fuel. Treatment options are limited if patients fail the ketogenic diet. We present a case of successful diazoxide use with continuous glucose monitoring in a patient with Glut1 deficiency syndrome who did not respond to the ketogenic diet.

Pediatric Obesity-Assessment, Treatment, and Prevention: An Endocrine Society Clinical Practice Guideline.

COSPONSORING ASSOCIATIONS: The European Society of Endocrinology and the Pediatric Endocrine Society. This guideline was funded by the Endocrine Society. OBJECTIVE: To formulate clinical practice guidelines for the assessment, treatment, and prevention of pediatric obesity. PARTICIPANTS: The participants include an Endocrine Society-appointed Task Force of 6 experts, a methodologist, and a medical writer. EVIDENCE: This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation approach to describe the strength of recommendations and the quality of evidence. The Task Force commissioned 2 systematic reviews and used the best available evidence from other published systematic reviews and individual studies. CONSENSUS PROCESS: One group meeting, several conference calls, and e-mail communications enabled consensus. Endocrine Society committees and members and co-sponsoring organizations reviewed and commented on preliminary drafts of this guideline. CONCLUSION: Pediatric obesity remains an ongoing serious international health concern affecting ∼17% of US children and adolescents, threatening their adult health and longevity. Pediatric obesity has its basis in genetic susceptibilities influenced by a permissive environment starting in utero and extending through childhood and adolescence. Endocrine etiologies for obesity are rare and usually are accompanied by attenuated growth patterns. Pediatric comorbidities are common and long-term health complications often result; screening for comorbidities of obesity should be applied in a hierarchal, logical manner for early identification before more serious complications result. Genetic screening for rare syndromes is indicated only in the presence of specific historical or physical features. The psychological toll of pediatric obesity on the individual and family necessitates screening for mental health issues and counseling as indicated. The prevention of pediatric obesity by promoting healthful diet, activity, and environment should be a primary goal, as achieving effective, long-lasting results with lifestyle modification once obesity occurs is difficult. Although some behavioral and pharmacotherapy studies report modest success, additional research into accessible and effective methods for preventing and treating pediatric obesity is needed. The use of weight loss medications during childhood and adolescence should be restricted to clinical trials. Increasing evidence demonstrates the effectiveness of bariatric surgery in the most seriously affected mature teenagers who have failed lifestyle modification, but the use of surgery requires experienced teams with resources for long-term follow-up. Adolescents undergoing lifestyle therapy, medication regimens, or bariatric surgery for obesity will need cohesive planning to help them effectively transition to adult care, with continued necessary monitoring, support, and intervention. Transition programs for obesity are an uncharted area requiring further research for efficacy. Despite a significant increase in research on pediatric obesity since the initial publication of these guidelines 8 years ago, further study is needed of the genetic and biological factors that increase the risk of weight gain and influence the response to therapeutic interventions. Also needed are more studies to better understand the genetic and biological factors that cause an obese individual to manifest one comorbidity vs another or to be free of comorbidities. Furthermore, continued investigation into the most effective methods of preventing and treating obesity and into methods for changing environmental and economic factors that will lead to worldwide cultural changes in diet and activity should be priorities. Particular attention to determining ways to effect systemic changes in food environments and total daily mobility, as well as methods for sustaining healthy body mass index changes, is of importance.

In Nonobese Girls, Waist Circumference as a Predictor of Insulin Resistance Is Comparable to MRI Fat Measures and Superior to BMI.

OBJECTIVE: The aim of this study was to investigate the degree to which waist circumference (WC), body mass index (BMI), and magnetic resonance imaging (MRI)-measured abdominal fat deposition predict insulin resistance (IR) in nonobese girls of diverse racial and ethnic backgrounds. METHODS: Fifty-seven nonobese girls (12 African-American, 16 Hispanic White, and 29 non-Hispanic White girls) aged 11-14 years were assessed for WC, MRI hepatic proton density fat fraction, visceral and subcutaneous adipose tissue volume, BMI Z-score, fasting insulin, homeostasis model of assessment (HOMA)-IR, adiponectin, leptin, sex hormone-binding globulin, high-density lipoprotein cholesterol, and triglycerides. RESULTS: Univariate and multivariate analyses adjusted for race and ethnicity indicated that only WC and visceral adipose tissue volume were independent predictors of fasting insulin and HOMA-IR, while hepatic proton density fat fraction, BMI Z-score, and subcutaneous adipose tissue volume were dependent predictors. Hispanic White girls showed significantly higher mean fasting insulin and HOMA-IR and lower sex hormone-binding globulin than non-Hispanic White girls (p < 0.01). CONCLUSIONS: In nonobese girls of diverse racial and ethnic backgrounds, WC, particularly when adjusted for race or ethnicity, is an independent predictor of IR comparable to MRI-derived measurements of fat and superior to the BMI Z-score.

Polyglandular autoimmune syndrome type I - a novel AIRE mutation in a North American patient.

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.

Predicting hepatic steatosis in a racially and ethnically diverse cohort of adolescent girls.

OBJECTIVE: To develop a risk assessment model for early detection of hepatic steatosis using common anthropometric and metabolic markers. STUDY DESIGN: This was a cross-sectional study of 134 adolescent and young adult females, age 11-22 years (mean 13.3±2 years) from a middle school and clinics in Madison, Wisconsin. The ethnic distribution was 27% Hispanic and 73% non-Hispanic; the racial distribution was 64% Caucasian, 31% African-American, and 5% Asian, Fasting glucose, fasting insulin, alanine aminotransferase (ALT), body mass index (BMI), waist circumference (WC), and other metabolic markers were assessed. Hepatic fat was quantified using magnetic resonance imaging proton density fat fraction (MR-PDFF). Hepatic steatosis was defined as MR-PDFF>5.5%. Outcome measures were sensitivity, specificity, and positive predictive value (PPV) of BMI, WC, ALT, fasting insulin, and ethnicity as predictors of hepatic steatosis, individually and combined, in a risk assessment model. Classification and regression tree methodology was used to construct a decision tree for predicting hepatic steatosis. RESULTS: MR-PDFF revealed hepatic steatosis in 16% of subjects (27% overweight, 3% nonoverweight). Hispanic ethnicity conferred an OR of 4.26 (95% CI, 1.65-11.04; P=.003) for hepatic steatosis. BMI and ALT did not independently predict hepatic steatosis. A BMI>85% combined with ALT>65 U/L had 9% sensitivity, 100% specificity, and 100% PPV. Lowering the ALT value to 24 U/L increased the sensitivity to 68%, but reduced the PPV to 47%. A risk assessment model incorporating fasting insulin, total cholesterol, WC, and ethnicity increased sensitivity to 64%, specificity to 99% and PPV to 93%. CONCLUSION: A risk assessment model can increase specificity, sensitivity, and PPV for identifying the risk of hepatic steatosis and guide the efficient use of biopsy or imaging for early detection and intervention.

Ethnic differences in the effects of hepatic fat deposition on insulin resistance in nonobese middle school girls.

OBJECTIVE: In nonobese youth, to investigate whether hepatic fat deposition and its metabolic consequences vary between ethnic groups. DESIGN AND METHODS: Thirty-two nonobese girls (12 Hispanic White [H] and 20 non-Hispanic White [NHW] girls), aged 11-14 years old were recruited. Outcome measures were MRI measured hepatic proton density fat fraction (hepatic PDFF), BMI Z-score, waist circumference, fasting insulin, glucose, adiponectin, sex hormone-binding globulin [SHBG], ALT, AST, triglycerides, and HOMA-IR. RESULTS: There were no significant differences in mean BMI Z-scores (P = 0.546) or hepatic PDFF (P = 0.275) between H and NHW girls; however, H girls showed significant correlations between hepatic PDFF and markers of IR (fasting insulin, HOMA-IR, adiponectin, SHBG, triglycerides; all P < 0.05), while NHW girls showed no significant correlations. Matched by hepatic PDFF or BMI Z-score, H girls had more evidence of IR for a given hepatic PDFF (mean insulin, HOMA-IR, and SHBG; all P < 0.05) or BMI Z-score (mean insulin and HOMA-IR; all P < 0.01) than NHW girls. CONCLUSIONS: In nonobese female youth, ethnicity-related differences in effects of hepatic fat on IR are evident, so that in H girls, a given amount of hepatic fat appears to result in a more predictable and greater degree of IR than in NHW girls.

Neonatal hypocalcemic seizures due to excessive maternal calcium ingestion.

Hypocalcemia is a common, treatable cause of neonatal seizures. A term girl neonate with no apparent risk factors developed seizures on day 5 of life, consisting of rhythmic twitching of all extremities in a migrating pattern. Physical examination was normal except for jitteriness. Laboratory evaluation was unremarkable except for decreased total and ionized serum calcium levels and an elevated serum phosphorus level. The mother had ingested 3-6 g of calcium carbonate daily during the final 4 months of pregnancy to control morning sickness. The baby's electroencephalogram showed multifocal interictal sharp waves and intermittent electrographic seizures consisting of focal spikes in the left hemisphere accompanied by rhythmic jerking of the right arm and leg. Treatment with intravenous calcium gluconate over several days resulted in cessation of seizures and normalization of serum calcium. The child has remained seizure free and is normal developmentally at 9 years of age. Hypocalcemic seizures in this newborn were likely secondary to excessive maternal calcium ingestion, which led to transient neonatal hypoparathyroidism and hypocalcemia. Inquiry about perinatal maternal medication use should include a search for over-the-counter agents that might not be thought of as "drugs," as in this case, antacids.

Oxandrolone Improves Height Velocity and BMI in Patients with Cystic Fibrosis.

Objective. To evaluate the effectiveness of oxandrolone in improving the nutritional status and linear growth of pediatric patients with cystic fibrosis (CF). Methods. Medical records of patients with CF treated with oxandrolone were reviewed for height z score, height velocity (HV), BMI z score, weight velocity (WV), Tanner stage, pulmonary function, liver enzyme levels, and any reported adverse events. Data were compared before (pre-Ox) and after (Ox) oxandrolone using a paired t-test. Results. 5 subjects (ages 8.5-14.5 years) were treated with oxandrolone 2.5 mg daily for 8-38 months. After 8-12 months of treatment, there was a statistically significant improvement in HV (pre-Ox = 5.3 +/- 1.4 cm/yr, Ox = 8.3 +/- 1.2 cm/yr, P < .01) and BMI z score (pre-Ox = -0.61 +/- 1.04, Ox = -0.30 +/- 0.86, P = .02). Both height z score (pre-Ox = -1.64 +/- 0.63, Ox = -1.30 +/- 0.49, P = .057) and WV (pre-Ox = 4.2 +/- 3.7 kg/yr, Ox = 6.8 +/- 1.0 kg/yr, P = .072) showed beneficial trends that did not reach statistical significance. No adverse events were reported. Conclusions. In this brief clinical report, oxandrolone improved the HV and BMI z score in patients with CF. Larger studies are needed to determine if oxandrolone is an effective, safe, and affordable option to stimulate appetite, improve weight gain, and promote linear growth in patients with CF.