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OBJECTIVE To identify and define clinically meaningful type 1 diabetes outcomes beyond hemoglobin A1c (HbA1c) based upon a review of the evidence, consensus from clinical experts, and input from researchers, people with type 1 diabetes, and industry. Priority outcomes include hypoglycemia, hyperglycemia, time in range, diabetic ketoacidosis (DKA), and patient-reported outcomes (PROs). While priority outcomes for type 1 and type 2 diabetes may overlap, type 1 diabetes was the focus of this work. RESEARCH AND METHODS A Steering Committee—comprising representatives from the American Association of Clinical Endocrinologists, the American Association of Diabetes Educators, the American Diabetes Association, the Endocrine Society, JDRF International, The Leona M. and Harry B. Helmsley Charitable Trust, the Pediatric Endocrine Society, and the T1D Exchange—was the decision-making body for the Type 1 Diabetes Outcomes Program. Their work was informed by input from researchers, industry, and people with diabetes through Advisory Committees representing each stakeholder group. Stakeholder surveys were used to identify priority outcomes. The outcomes prioritized in the surveys were hypoglycemia, hyperglycemia, time in range, DKA, and PROs. To develop consensus on the definitions of these outcomes, the Steering Committee relied on published evidence, their clinical expertise, and feedback from the Advisory Committees. RESULTS The Steering Committee developed definitions for hypoglycemia, hyperglycemia, time in range, and DKA in type 1 diabetes. The definitions reflect their assessment of the outcome’s short- and long-term clinical impact on people with type 1 diabetes. Knowledge gaps to be addressed by future research were identified. The Steering Committee discussed PROs and concluded that further type 1 diabetes–specific development is needed. CONCLUSIONS The Steering Committee recommends use of the defined clinically meaningful outcomes beyond HbA1c in the research, development, and evaluation of type 1 diabetes therapies.

AIMS: Increased adiposity is a risk factor for suboptimal diabetes control and cardiovascular disease (CVD) complications. Our goal was to identify modifiable behavioral characteristics of overweight and obese pediatric patients with type 1 diabetes mellitus (T1DM) who achieve optimal glycemic control and to evaluate their CVD risk compared to lean patients. Our hypothesis was that optimally controlled obese and overweight participants require more total daily insulin and are at higher CVD risk compared to optimally controlled lean participants. METHODS: We analyzed a cohort of 9,263 participants with T1DM aged

The asymptomatic phase of type 1 diabetes is recognised by the presence of beta cell autoantibodies in the absence of hyperglycaemia. We propose that an accurate description of this stage is provided by the name 'Autoimmune Beta Cell Disorder' (ABCD). Specifically, we suggest that this nomenclature and diagnosis will, in a proactive manner, shift the paradigm towards type 1 diabetes being first and foremost an immune-mediated disease and only later a metabolic disease, presaging more active therapeutic intervention in the asymptomatic stage of disease, before end-stage beta cell failure. Furthermore, we argue that accepting ABCD as a diagnosis will be critical in order to accelerate pharmaceutical, academic and public activities leading to clinical trials that could reverse beta cell autoimmunity and halt progression to symptomatic insulin-requiring type 1 diabetes. We recognize that there are both opportunities and challenges in the implementation of the ABCD concept but hope that the notion of 'asymptomatic autoimmune disease' as a disorder will be widely discussed and eventually accepted. ispartof: Diabetologia vol:60 issue:1 pages:35-38 ispartof: location:Germany status: published

Background: This feasibility study investigated the insulin-delivery characteristics of the Hypoglycemia-Hyperglycemia Minimizer (HHM) System—an automated insulin delivery device—in participants with type 1 diabetes. Methods: Thirteen adults with type 1 diabetes were enrolled in this nonrandomized, uncontrolled, clinical-research-center-based feasibility study. The HHM System comprised a continuous subcutaneous insulin infusion pump, a continuous glucose monitor (CGM), and a model predictive control algorithm with a safety module, run on a laptop platform. Closed-loop control lasted approximately 20 hours, including an overnight period and two meals. Results: When attempting to minimize glucose excursions outside of a prespecified target zone, the predictive HHM System decreased insulin infusion rates below the participants’ preset basal rates in advance of below-zone excursions (CGM < 90 mg/dl), and delivered 80.4% less insulin than basal during those excursions. Similarly, the HHM System increased infusion rates above basal during above-zone excursions (CGM > 140 mg/dl), delivering 39.9% more insulin than basal during those excursions. Based on YSI, participants spent a mean ± standard deviation (SD) of 0.2 ± 0.5% of the closed-loop control time at glucose levels < 70 mg/dl, including 0.3 ± 0.9% for the overnight period. The mean ± SD glucose based on YSI for all participants was 164.5 ± 23.5 mg/dl. There were nine instances of algorithm-recommended supplemental carbohydrate administrations, and there was no severe hypoglycemia or diabetic ketoacidosis. Conclusions: Results of this study indicate that the current HHM System is a feasible foundation for development of a closed-loop insulin delivery device.

Safe and widespread use of diabetes technology is constrained by alarm fatigue: When someone receives so many alarms that he or she becomes less likely to respond appropriately. Alarm fatigue and related usability issues deserve consideration at every stage of alarm system design, especially as new technologies expand the potential number and complexity of alarms. The guiding principle should be patient wellbeing, while taking into consideration the regulatory and liability issues that sometimes contribute to building excessive alarms. With examples from diabetes devices, we illustrate two complementary frameworks for alarm design: A “patient safety first” perspective and a focus on human factors. We also describe opportunities and challenges that will come with new technologies such as remote monitoring, adaptive alarms, and ever-closer integration of glucose sensing with insulin delivery.

Objective: This study aims to compare the effectiveness of insulin glargine 300 U/mL (Gla-300) with its accompanying patient support program with that of other basal insulin and available patient support programs in patients with type 2 diabetes (T2D) in a real-world setting in terms of achieving HEDIS (Healthcare Effectiveness Data and Information Set) individualized glycemic targets without documented symptomatic hypoglycemia. Methods: Achieve Control is a US-based, multicenter, randomized, open-label, active-controlled, parallel group pragmatic Phase IV trial in insulin-naïve patients with T2D uncontrolled on ≥2 oral antidiabetes drugs (OAD) and/or glucagon-like peptide-1 receptor antagonists (GLP-1 RA). Inclusion criteria include a diagnosis of T2D, age ≥18 years, and glycated hemoglobin (HbA1c) between 8.0% and 11.0%. Patients will be assigned to either the Gla-300 or other basal insulin group. The primary end point is the proportion of patients achieving HEDIS HbA1c targets (Conclusion: Pragmatic clinical trials offer the potential to assess comparative effectiveness in broadly based patient populations receiving care (with or without a corresponding educational support program) in real-world clinical settings. The results of Achieve Control should elucidate the benefits of management of T2D with Gla-300 versus other basal insulins in terms of patient outcomes, experiences, and perceptions, and its impact on healthcare resource utilization and cost. Clinical trial registration: www.clinicaltrials.gov identifier is NCT02451137.

Barriers to continuous glucose monitoring (CGM) use continue to hamper adoption of this valuable technology for the management of diabetes. The American Association of Clinical Endocrinologists and the American College of Endocrinology convened a public consensus conference February 20, 2016, to review available CGM data and propose strategies for expanding CGM access.Conference participants agreed that evidence supports the benefits of CGM in type 1 diabetes and that these benefits are likely to apply whenever intensive insulin therapy is used, regardless of diabetes type. CGM is likely to reduce healthcare resource utilization for acute and chronic complications, although real-world analyses are needed to confirm potential cost savings and quality of life improvements. Ongoing technological advances have improved CGM accuracy and usability, but more innovations in human factors, data delivery, reporting, and interpretation are needed to foster expanded use. The development of a standardized data report using similar metrics across all devices would facilitate clinician and patient understanding and utilization of CGM. Expanded CGM coverage by government and private payers is an urgent need.CGM improves glycemic control, reduces hypoglycemia, and may reduce overall costs of diabetes management. Expanding CGM coverage and utilization is likely to improve the health outcomes of people with diabetes.A1C = glycated hemoglobin AACE = American Association of Clinical Endocrinologists ACE = American College of Endocrinology ASPIRE = Automation to Simulate Pancreatic Insulin Response CGM = continuous glucose monitoring HRQOL = health-related quality of life ICER = incremental cost-effectiveness ratio JDRF = Juvenile Diabetes Research Foundation MARD = mean absolute relative difference MDI = multiple daily injections QALY = quality-adjusted life years RCT = randomized, controlled trial SAP = sensor-augmented pump SMBG = self-monitoring of blood glucose STAR = Sensor-Augmented Pump Therapy for A1C Reduction T1D = type 1 diabetes T2D = type 2 diabetes.

Much progress has been made in diabetes treatments since the first dose of insulin was administered in 1921. However, a truly transformational moment in diabetes care occurred when urine testing gave way to capillary blood home glucose monitoring. As improvements were made to these devices, continuous glucose monitoring (CGM) was introduced. The advantages of experiential learnings gleaned from seeing continuous real-time data have been borne out in numerous peer-reviewed journals. Limitations to use of CGM include patient's level of numeracy and literacy, development of alarm fatigue, interfering substances leading to erroneous readings, high rates of discontinuation, and poor reimbursement.

Although GH has been used to treat short stature in GH deficiency (GHD) and other conditions for more than 40 yr, criteria for satisfactorily defining targets for GH responsiveness have never been developed.The objective of this study was to present the first-year growth expressed as height velocity (HV) for prepubertal boys and girls with idiopathic GHD, organic GHD, idiopathic short stature, or Turner syndrome from Genentech's National Cooperative Growth Study to derive age-specific targets for GH responsiveness for each etiology and gender.Using data from the National Cooperative Growth Study, we constructed curves of response to GH during the first year of treatment with standard daily doses in naive-to-treatment prepubertal children with idiopathic GHD (2323 males, 842 females), organic GHD (582 males, 387 females), idiopathic short stature (1392 males, 465 females), or Turner syndrome (1367 females).For each category, mean pretreatment and mean +/-1 and +/-2 sd for the first-year HV on GH were assessed. Mean and mean +/- 1 sd for HV were plotted vs. age at baseline (initiation of GH treatment) and compared with mean pretreatment HV.HV plots for each category as a factor of age at baseline are presented. Mean - 2 sd HV plots approximated the pretreatment HV.Using baseline age- and gender-specific targets will assist clinicians in assessing a patient's first-year growth response. We propose that HV below the mean - 1 sd on these plots be considered a "poor" response. These curves may be used to identify patients who may benefit from GH dose adjustment, to assess compliance issues, or to challenge the original diagnosis.

Background: Oxidative stress is a detrimental feature of diabetes implicated in the progression of the disease and its complications. The relationship between insulin therapy and oxidative stress is complex. This study tested the hypothesis that improved glucose control, rather than insulin dose, is central to reduced oxidative stress in patients with type 2 diabetes following continuous subcutaneous insulin infusion (CSII). Methods: In this 16-week, multicenter study, 54 CSII-naïve patients with type 2 diabetes (age 57 ± 10 years, HbA1c 69 ± 15 mmol/mol [8.5 ± 1.4%], diabetes duration 13 ± 6 years) treated with either oral antidiabetic agents (OAD) alone (n = 17), basal insulin ± OAD (n = 17), or multiple daily injections (MDI) ± OAD (n = 20) were the evaluable group. Diabetes medications except metformin were discontinued, and 16 weeks of CSII was initiated. Insulin dose was titrated to achieve optimal glycemic control. A plasma marker of oxidative stress relevant to cardiovascular disease (oxidized low density lipoprotein [ox-LDL]) was assessed at baseline and week 16. Results: CSII improved glycemic control (HbA1c −13 ± 2 mmol/mol [−1.2 ± 0.2%]; fasting glucose −36.6 ± 8.4 mg/dL; mean glucose excursion −23.2 ± 6.5 mg/dL, mean ± SE; all P < .001) and reduced ox-LDL (–10.5%; P < .05). The antioxidant effect was cohort-independent ( P > .05), but was significantly more pronounced in patients on statins ( P = .019). The effect of CSII was more closely correlated to improvements in glucose excursion ( P = .013) than to insulin dose ( P > .05) or reduction in HbA1c ( P > .05). Conclusions: CSII induces depression of plasma ox-LDL associated with change in glucose control, rather than with change in insulin dose. The effect is augmented in patients receiving statins.

Context: LHX3 encodes LIM homeodomain class transcription factors with important roles in pituitary and nervous system development. The only previous report of LHX3 mutations described patients with two types of recessive mutations displaying combined pituitary hormone deficiency coupled with neck rigidity.Objective: We report a patient presenting a unique phenotype associated with a novel mutation in the LHX3 gene.Patient: We report a 6-yr, 9-month-old boy born from a consanguineous relationship who presented shortly after birth with cyanosis, feeding difficulty, persistent jaundice, micropenis, and poor weight gain and growth rate. Laboratory data, including an undetectable TSH, low free T4, low IGF-I and IGF binding protein-3, prolactin deficiency, and LH and FSH deficiency were consistent with hypopituitarism. A rigid cervical spine leading to limited head rotation was noticed on follow-up examination. Magnetic resonance imaging revealed an apparently structurally normal cervical spine and a postcontrast hypointense lesion in the anterior pituitary.Results: Analysis of the LHX3 gene revealed homozygosity for a novel single-base-pair deletion in exon 2. This mutation leads to a frame shift predicted to result in the production of short, inactive LHX3 proteins. The results of in vitro translation experiments are consistent with this prediction. The parents of the patients are heterozygotes, indicating a recessive mode of action for the deletion allele.Conclusions: The presence of a hypointense pituitary lesion and other clinical findings broadens the phenotype associated with LHX3 gene mutation.

In March 2004 a group of 65 physicians and other health professionals representing nine countries on four continents convened in Israel to discuss the widespread public health crisis in childhood obesity. Their aim was to explore the available evidence and develop a consensus on the way forward. The process was rigorous, although time and resources did not permit the development of formal evidence-based guidelines. In the months before meeting, participants were allocated to seven groups covering prevalence, causes, risks, prevention, diagnosis, treatment, and psychology. Through electronic communication each group selected the key issues for their area, searched the literature, and developed a draft document. Over the 3-d meeting, these papers were debated and finalized by each group before presenting to the full group for further discussion and agreement. In developing a consensus statement, this international group has presented the evidence, developed recommendations, and provided a platform aimed toward future corrective action and ongoing debate in the international community.

Background: The Hypoglycemia-Hyperglycemia Minimizer (HHM) System aims to mitigate glucose excursions by preemptively modulating insulin delivery based on continuous glucose monitor (CGM) measurements. The “aggressiveness factor” is a key parameter in the HHM System algorithm, affecting how readily the system adjusts insulin infusion in response to changing CGM levels. Methods: Twenty adults with type 1 diabetes were studied in closed-loop in a clinical research center for approximately 26 hours. This analysis focused on the effect of the aggressiveness factor on the insulin dosing characteristics of the algorithm and, to a lesser extent, on the glucose control results observed. Results: As the aggressiveness factor increased from conservative to medium to aggressive: the maximum observed insulin dose delivered by the algorithm—which is designed to give doses that are corrective in nature every 5 minutes—increased (1.00 vs 1.15 vs 2.20 U, respectively); tendency to adhere to the subject’s nominal basal dose decreased (61.9% vs 56.6% vs 53.4%); and readiness to decrease insulin below basal also increased (18.4% vs 19.4% vs 25.2%). Glucose analyses by both CGM and Yellow Springs Instruments (YSI) indicated that the aggressive setting of the algorithm resulted in the least time spent at levels >180 mg/dL, and the most time spent between 70-180 mg/dL. There was no severe hyperglycemia, diabetic ketoacidosis, or severe hypoglycemia for any of the aggressiveness values investigated. Conclusions: These analyses underscore the importance of investigating the sensitivity of the HHM System to its key parameters, such as the aggressiveness factor, to guide future development decisions.

The newborn whose genitalia are ambiguous presents a challenge to the pediatrician and the family. A clear understanding of the basis of sex differentiation and timely consultation with a pediatric endocrinologist is critical in the evaluation and determination of sex of rearing in a newborn who has ambiguous genitalia. Sex karyotype and a 17-OHP level may suffice in the initial evaluation of female pseudohermaphroditism because most patients will have virilizing CAH. If male pseudohermaphroditism is suspected on the basis of palpable gonads, we routinely obtain a karyotype, basal adrenal steroid levels, and levels of hCG-stimulated serum testosterone and DHT, then consider a testosterone treatment trial. Physicians who care for children who have ambiguous genitalia must appreciate the family's cultural, religious, and psychological needs and avoid determining sex of rearing before accurate diagnosis is reached.

BACKGROUND AND AIM In the context of present epidemic of childhood obesity, we aimed to find the prevalence of nonalcoholic fatty liver disease (NAFLD) and metabolic syndrome (MS) in a cohort of obese children. METHODOLOGY Retrospective chart analysis of 700 obese children was done for their anthropometric and biochemical investigations. RESULTS Some 15.4% (9.8% girls, 22% boys) subjects had NAFLD (ALT > 40 IU/L) after excluding other identifiable causes of liver dysfunction. Age, weight, TG, fasting serum insulin and HOMA-IR levels were higher in children with NAFLD. Twenty-eight percent children had MS. Children with NAFLD had an odds ratio of 2.65 for having MS (boys 4.6, girls 1.7). The prevalence of MS increased with age 5-9 years (21%), 10-16 years (30%), 17-20 years (35%). CONCLUSION Given high prevalence of NAFLD and MS in obese children, childhood obesity should be seriously considered as a disease and not just a cosmetic issue.

Introduction While the endogenous first-phase insulin response has disappeared by the time of diagnosis of type 1 diabetes mellitus (T1DM), anecdotal evidence suggests that these patients can continue to have a second-phase insulin response during the first 12 months after diagnosis. We hypothesized that patients who are started on continuous subcutaneous insulin infusion (CSII) at the time of diagnosis of T1DM would have a lower basal insulin requirement than the 40-60% usually expected. Methods We analyzed 38 patients with T1DM, age 9.9 +/- 6.4 years, 71% male, who were started on CSII within the first month of diagnosis. Results Average basal insulin requirements were 47-49% of total daily dose during the first 12 months after diagnosis and decreased from 0.30 U/kg/day at diagnosis to 0.20 U/kg/day by 12 months. Baseline percentage of basal insulin was significantly correlated with hemoglobin A1c at baseline and at six months. The percentage of basal insulin requirement at 12 months after diagnosis was significantly correlated with baseline body mass index (BMI) and current BMI. No other correlations between percentage of basal insulin requirements and any other factors were seen. Conclusion Our data suggest that, even though some endogenous insulin production remains during the first year after diagnosis of T1DM, the distribution of basal versus total daily insulin requirements remains the same as in the general population of people with diabetes. There may be benefits to starting patients on a higher basal rate at time of diagnosis for overall glycemic control during the first six months. Further research is needed to optimize starting insulin doses to maximize their potential in preserving beta-cell function.

Steady progress is being made toward the development of a so-called "artificial pancreas," which may ultimately be a fully automated, closed-loop, glucose control system comprising a continuous glucose monitor, an insulin pump, and a controller. The controller will use individualized algorithms to direct delivery of insulin without user input. A major factor propelling artificial pancreas development is the substantial incidence of-and attendant patient, parental, and physician concerns about-hypoglycemia and extreme hyperglycemia associated with current means of insulin delivery for type 1 diabetes mellitus (T1DM). A successful fully automated artificial pancreas would likely reduce the frequency of and anxiety about hypoglycemia and marked hyperglycemia. Patch-pump systems ("patch pumps") are likely to be used increasingly in the control of T1DM and may be incorporated into the artificial pancreas systems of tomorrow. Patch pumps are free of tubing, small, lightweight, and unobtrusive. This article describes features of patch pumps that have been approved for U.S. marketing or are under development. Included in the review is an introduction to control algorithms driving insulin delivery, particularly the two major types: proportional integrative derivative and model predictive control. The use of advanced algorithms in the clinical development of closed-loop systems is reviewed along with projected next steps in artificial pancreas development.

Background: McCune-Albright syndrome (MAS) typically comprises the constellation of polyostotic fibrous dysplasia, café-au-lait spots, and associated endocrinopathies including gonadotropin-independent precocious puberty, excessive growth hormone production and gigantism, hyperthyroidism, and hyperparathyroidism. Objective: We report the unique case of a boy with the diagnostic criteria of MAS accompanied by atypical short stature and macroorchidism without precocious puberty. Patient: An 8.4-year-old prepubertal boy presented with a history of recurrent bone fractures, multiple café-au-lait spots, bilateral macroorchidism, and short stature. X-ray of the extremities was consistent with polyostotic fibrous dysplasia. Serum inhibin B (IB) and anti-müllerian hormone (AMH) were elevated; testosterone, LH, and FSH were normal for age. Results: PCR-based DNA analysis of bone tissue revealed a substitution of arginine for cysteine at position 201 in the Gsα protein resulting in activation of the Gsα subunit. Conclusions: We report a second case of MAS associated with macroorchidism. In this case, isolated Sertoli cell hyperfunction was also associated with microlithiasis and was not associated with peripheral precocious puberty. Short stature not associated with GH-IGF-1 axis abnormality was a second anomalous finding in this case. Our experience suggests that the phenotypic variation in MAS is wider than previously described.

UNLABELLED Alstrom syndrome (AS) is an autosomal recessive disorder characterized by progressive pigmentary retinopathy, sensorineural hearing loss, fatty liver infiltration, obesity, insulin resistance and early-onset type 2 diabetes mellitus (DM2). Early onset of insulin resistance and DM2 are key components of this syndrome. AIM To study the effect of early initiation of the insulin sensitizer metformin combined with rosiglitazone in a patient with AS with impaired glucose tolerance. PATIENT An 8 year-old boy with AS presented with acanthosis nigricans and insulin resistance at the age of 6 years. He had progressive excessive weight gain from 9 months of age. By the age of 1 year he developed photosensitivity, blindness and nystagmus. At the age of 5.5 years, his body mass index (BMI) was above the 95th percentile. He developed impaired glucose tolerance at 6 years of age and treatment with metformin was initiated. After 8 months of treatment with metformin he developed DM2. The dose of metformin was increased, and rosiglitazone added. METHODS A 2-hour oral glucose tolerance test (OGTT) and a rapid intravenous glucose tolerance test (IVGTT) were performed before treatment was initiated, after treatment with metformin and at the end of 1 year of combination therapy with metformin and rosiglitazone to calculate quantitative insulin sensitivity check index (QUICKI) and acute insulin response (AIR). For mutation analysis, all exons and splice site sequences of the ALMS1 gene were amplified and sequenced. RESULTS Metformin treatment alone at the stage of impaired glucose tolerance did not prevent progression to DM2. However, metformin at a higher dose and in combination with rosiglitazone resulted in improvement of pancreatic beta-cell function, shown by markedly improved first-phase insulin response to glucose measured by AIR. The patient was found to have two heterozygous nonsense mutations in ALMS1, 8008 C-->T Ter, R2670X, and 11449 C-->T Ter, Q3817X. These alterations cause premature stops and result in a truncated ALMS1 protein. CONCLUSION We suggest that early initiation of combined therapy comprising a high dose of metformin plus rosiglitazone may be valuable in managing insulin resistance and DM2 in children with AS.

Objective: Recent studies have shown a broad prevalence of vitamin D deficiency in adults. Serum 25-hydroxyvitamin D (25-OHD) levels were reported to be inversely related to body mass index (BMI) and body fat content and correlated directly with hypertension, degree of insulin resistance and progression to diabetes mellitus. We sought to determine the prevalence of vitamin D insufficiency and markers of metabolic syndrome in an obese pediatric population. Methods: Charts of 217 obese (weight >95 th percentile for age and sex) children (118 females, 99 males; mean BMI 32.2 ± 6.4 kg/m 2 ; mean age 12.9 ± 5.5; age range 7-18 years) who had received a standard physical examination at the pediatric endocrine clinic of the Infants and Children's Hospital of Brooklyn at Maimonides, Brooklyn, NY, were retrospectively analyzed. Data obtained included age, sex, weight, BMI, height and systolic and diastolic blood pressure. The routine bloodwork panel for obesity at our pediatric endocrine facility includes fasting 25-OHD, total cholesterol, high density lipoprotein-cholesterol (HDL-C), low density lipoprotein-cholesterol (LDL-C), triglycerides, ALT, AST, thyroid stimulating hormone (TSH), total T 4 , and insulin and glucose. Insulin sensitivity as calculated by quantitative insulin-sensitivity check index (QUICKI = 1/[log(I 0 ) + log(Go)], where I 0 is fasting insulin and Go is fasting glucose) was computed following the visit. Results: Overall, 55.2% of patients were vitamin D insufficient (25-OHD

This study was designed to test the feasibility and efficacy of continuous subcutaneous insulin infusion (CSII) being instituted within 1 month of diagnosis of type 1 diabetes mellitus (T1DM).Twenty-eight consecutive patients with newly diagnosed T1DM with a mean age of 12.1 +/- 6.2 years were placed on CSII, as early as within 1 day of their diagnosis. All accepted CSII when offered it, and none elected to discontinue CSII after follow-up periods of up to 3 years.Hemoglobin A1c levels declined from an initial mean of 10.5 +/- 2.4% to between 6.5% and 7.4% over the next 18 months, at a mean insulin requirement of 0.33 units/kg/day at 3 months, which gradually rose to 0.58 units/kg/day by 18 months. Endogenous insulin secretion, measured by C-peptide values, remained stable during the first 12 months after diagnosis. There was no significant weight gain for the duration of the study (20.7 kg/m(2) vs. a peak of 22.1 kg/m(2) at 12 months, P = 0.54).The study provided a positive experience with CSII as the initial insulin replacement therapy in newly diagnosed patients with T1DM with excellent clinical outcomes and apparent prolongations of the honeymoon period. It remains to be proven by random patient assignment whether endogenous insulin secretion is better preserved with CSII as an initial ongoing treatment modality and whether long-term complications are reduced by this approach.

The role of growth hormone (GH) in obesity is controversial. Childhood obesity is characterized by reduced GH secretion. Low, high and normal serum insulin-like growth factor-I (IGF-I) levels have been described in obese children in the face of low GH secretion. There is conflicting information on the interaction of GH and obesity upon components of the GH-IGF-I-insulin-like growth factor binding proteins (IGFBPs) system and its relationship to cardiovascular risk factors.This review highlights the role of GH modulating cardiovascular risk factors, including lipid levels, inflammatory markers, cardiac and endothelial function in children and adolescents with obesity and insulin resistance.The interplay between GH secretion, NO production, IGF-I, IGFBP-1, and IGFBP-3 levels, lipid profile, insulin sensitivity and the degree of visceral obesity necessitates further study. These metabolic parameters may be useful markers of premature atherosclerosis in children with obesity. Further studies should address the question of optimal dose and duration of GH therapy in non-GH deficient obese patients with metabolic disturbances at risk for premature atherosclerosis.

Congenital lipoid adrenal hyperplasia (lipoid CAH) is an autosomal recessive disorder characterized by severe adrenal insufficiency and male sex reversal. Lipoid CAH is caused by mutations in two proteins that are essential for all steroid biosynthesis, the steroidogenic acute regulatory (StAR) protein and cytochrome P450scc. In this review, we discuss the clinical presentation and mechanisms behind the pathology of this fatal disorder.

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.

LHX3 encodes LIM homeodomain class transcription factors with important roles in pituitary and nervous system development. The only previous report of LHX3 mutations described patients with two types of recessive mutations displaying combined pituitary hormone deficiency coupled with neck rigidity.We report a patient presenting a unique phenotype associated with a novel mutation in the LHX3 gene.We report a 6-yr, 9-month-old boy born from a consanguineous relationship who presented shortly after birth with cyanosis, feeding difficulty, persistent jaundice, micropenis, and poor weight gain and growth rate. Laboratory data, including an undetectable TSH, low free T4, low IGF-I and IGF binding protein-3, prolactin deficiency, and LH and FSH deficiency were consistent with hypopituitarism. A rigid cervical spine leading to limited head rotation was noticed on follow-up examination. Magnetic resonance imaging revealed an apparently structurally normal cervical spine and a postcontrast hypointense lesion in the anterior pituitary.Analysis of the LHX3 gene revealed homozygosity for a novel single-base-pair deletion in exon 2. This mutation leads to a frame shift predicted to result in the production of short, inactive LHX3 proteins. The results of in vitro translation experiments are consistent with this prediction. The parents of the patients are heterozygotes, indicating a recessive mode of action for the deletion allele.The presence of a hypointense pituitary lesion and other clinical findings broadens the phenotype associated with LHX3 gene mutation.

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.We describe three new cases of lipoid CAH caused by novel mutations in the StAR gene.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.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.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.

Objectives. Bone mass increases throughout childhood, with maximal bone mass accrual rate occurring in early to mid-puberty and slowing in late puberty. Prevention of osteoporosis and its morbidities depends primarily on the establishment of adequate peak bone mass. Physical activity, calcium intake, and vitamin D stores (from sunlight conversion of precursors of vitamin D and to a lesser degree from dietary intake) are vital determinants of bone mineral density (BMD). BMD is further controlled by genetic and environmental factors that are poorly understood. Observance of ultra-Orthodox Jewish customs may have a negative effect on the factors that promote bone health, and there have been anecdotal reports of higher fracture rates in this population. The ultra-Orthodox Jewish lifestyle encourages scholarly activity in preference to physical activity. Additionally, modest dress codes and inner-city dwelling reduce sunlight exposure. Orthodox Jews do not consume milk products for 6 hours after meat ingestion, leading to potentially fewer opportunities to consume calcium. Foods from the milk group are some of the best sources of dietary calcium. Our aims are to examine BMD in a group of healthy ultra-Orthodox Jewish adolescents in an urban community and to attempt to correlate it to physical activity and dietary factors. Design and Methods. We recruited 50 healthy, ultra-Orthodox Jews, ages 15 to 19 years (30 males and 20 females). None were taking corticosteroids or had evidence of malabsorption. All girls were postmenarchal and nulliparous. Pubic hair Tanner stage for boys and breast Tanner stage for girls were determined. Weight and height standard deviation scores were calculated. Calcium, phosphorus, protein, vitamin D, and calorie intake were assessed using a comprehensive food questionnaire referring to what has been eaten over the last year. Hours per week of weight-bearing exercise and walking were determined. Serum levels of calcium, intact parathyroid hormone (PTH), 25 hydroxyvitamin D (25[OH]D) and 1,25 dihydroxyvitamin D (1,25[OH]2D) were measured. Lumbar spine (L) BMD was assessed by dual energy radiograph absorptiometry. The pediatric software supplied by Lunar Radiation Corporation, which contains gender- and age-specific norms, provided az score for the lumbar BMD for each participant. L2 to L4 bone mineral apparent density (BMAD) was calculated from L2 to L4 BMD. Results. BMD of L2 to L4 was significantly decreased compared with age/sex-matched normative data: mean zscore was −1.25 ± 1.25 (n = 50). The mean L2 to L4 BMD z score ± standard deviation was −1.71 ± 1.18 for boys and −0.58 ± 1.04 for girls. Eight boys (27%) had L2 to L4 BMD z scores The mean serum 25(OH)D level was 18.4 ± 7.6 ng/mL, and the mean serum 1,25(OH)2D level was 71.1 ± 15.7 pg/mL (n = 50). Boys had significantly higher serum levels of 1,25(OH)2D than did girls (74.9 ± 16.46 pg/mL vs 65.25 ± 12.8 pg/mL, respectively). The serum levels of PTH, calcium, and protein were (mean ± standard deviation): 33 ± 16 pg/mL, 9.5 ± 0.69 mg/dL, and 7.8 ± 0.6 g/dL, respectively (n = 50). L2 to L4 BMD z score had positive correlation with walking hours (r = 0.4). L2 to L4 BMDz score had negative correlation with serum level of 1,25(OH)2D )r = −0.33;n = 50). We could not find significant correlation between L2 to L4 BMD z scores for the entire cohort and any of calcium, vitamin D, phosphorus, or protein intake. However, the L2 to L4 BMD z scores of boys had positive correlation with calcium, phosphorus, and protein intake (r = 42, r = 44, and r = 43, respectively). After adjustment for Tanner stage, boys who had Tanner stage V (n = 16) had stronger positive correlation between L2 to L4 BMD z scores and calcium and protein intake (r = 0.55 and r = 0.57, respectively), as was the correlation between L2 to L4 BMDz score and weight-bearing activity and walking hours (r = 0.77 and r = 0.72, respectively; n = 16). By multiple regression analysis with stepwise selection, sex, walking hours, weight-standard deviation scores, and serum PTH predicted 54% of the variability in L2 to L4 BMD z score. Sex, walking hours, and age predicted 65% of the variability in L2 to L4 BMAD. Conclusions. Lumbar BMD is significantly decreased in ultra-Orthodox Jewish adolescents living in an urban community. Boys had profoundly lower spinal BMD than did girls. Previous studies have introduced estrogen as a critical factor in bone mineralization. However, the role of estrogen is still controversial. Our investigation of the significant determinants of BMD proved that sex is an important predictor of z score in this group, which may indicate the importance of sex hormones. Walking activity was positively associated with L2 to L4 BMDz score and was a significant predictor of L2 to L4 BMDz score and L2 to L4 BMAD. Additional studies are needed to investigate whether walking activity is lacking or is a causal factor of low BMD. The high normal levels of 1,25(OH)2D may represent a compensatory mechanism to absorb more calcium from the intestine, and the low normal 25(OH)D levels may represent relatively poor total body stores of vitamin D in this group of adolescents. This group is at great risk for the morbidities of poor bone health if no bone mineral recovery happens later in their life. We encourage additional longitudinal studies to evaluate the bone mineral status of the elder generation of this community and possible interventions that will lead to improved BMD. We recommend an increase in calcium intake to reach the adequate intake and an increase in walking activity. However, our study provides no evidence that following these recommendations will improve the BMD of this particular population.

Publisher Summary This chapter focuses on sex chromosome aberrations and genetic consequences. High resolution chromosomal banding allows for the identification of each human chromosome and the elucidation of complex chromosomal abnormalities and rearrangements. Aneuploidy describes a cell with the total number of chromosomes different from those normally found. Mechanisms responsible for aneuploidy include nondisjunction or anaphase lag occurring during meiosis or mitosis. Nondisjunction occurs when homologous chromosomes fail to separate during anaphase, resulting in one daughter cell with too numerous chromosomes and one daughter cell with too few. Anaphase lag occurs when one chromosome is lost from one or both daughter cells as a result of poor alignment during metaphase. The existence of two cell lines of different genetic origins in one individual is termed chimerism. Postulated mechanisms for this phenomenon include double fertilization of a binucleate ovum, fusion of two fertilized ova prior to implantation, and fertilization of an ovum and its polar body by separate sperm. Structural abnormalities in chromosomes usually occur as a result of chromosomal breakage and consequent fragment rearrangement or loss of chromosomal material.

Reported Parental Heights Do Not Differ from Actual Heights in an Outpatient Pediatric Endocrine Clinic in Brooklyn

Sir.—Primary care clinicians must offer anticipatory guidance to parents regarding separation and care of the umbilical stump. Most cords uneventfully separate within 5 to 14 days of birth.1,2The exact mechanism of cord separation is unknown; however, a combination of factors may contribute to its timing. Bacterial colonization, drying, necrosis, infarction, and granulocyte influx all influence cord separation, independently or in conjunction with one another. Prolonged retention of the umbilical cord may be a source of concern and anxiety to both parents and physicians. Some authors note that delayed separation may be associated with serious disorders of neutrophil function3,4,5and histiocytosis.6The following case of an infant with unusually delayed separation (10 weeks) prompted a literature review for guidance regarding management options. As the published information is scant and contradictory, we conducted a poll of practicing pediatricians to evaluate their preferences in managing these cases. Patient