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Islet autoantibodies can be detected prior to the onset of type 1 diabetes and are important tools for aetiologic studies, prevention trials and disease screening. Current risk stratification models rely on the positivity status of islet autoantibodies alone, but additional autoantibody characteristics may be important for understanding disease onset. This work aimed to determine if a data-driven model incorporating characteristics of islet autoantibody development, including timing, type and titre, could stratify risk for type 1 diabetes onset.Data on autoantibodies against GAD (GADA), tyrosine phosphatase islet antigen-2 (IA-2A) and insulin (IAA) were obtained for 1,415 children enrolled in The Environmental Determinants of Diabetes in the Young study with at least one positive autoantibody measurement from years 1 to 12 of life. Unsupervised machine learning algorithms were trained to identify clusters of autoantibody development based on islet autoantibody timing, type and titre. Risk for type 1 diabetes across each identified cluster was evaluated using time-to-event analysis.We identified 2-4 clusters in each year cohort that differed by autoantibody timing, titre and type. During the first 3 years of life, risk for type 1 diabetes onset was driven by membership in clusters with high titres of all three autoantibodies (1-year risk: 20.87-56.25%, 5-year risk: 67.73-69.19%). Type 1 diabetes risk transitioned to type-specific titres during ages 4 to 8, as clusters with high titres of IA-2A (1-year risk: 20.88-28.93%, 5-year risk: 62.73-78.78%) showed faster progression to diabetes compared with high titres of GADA (1-year risk: 4.38-6.11%, 5-year risk: 25.06-31.44%). The importance of high GADA titres decreased during ages 9 to 12, with clusters containing high titres of IA-2A alone (1-year risk: 14.82-30.93%) or both GADA and IA-2A (1-year risk: 8.27-25.00%) demonstrating increased risk.This unsupervised machine learning approach provides a novel tool for stratifying risk for type 1 diabetes onset using multiple autoantibody characteristics. These findings suggest that age-dependent changes in IA-2A titres modulate risk for type 1 diabetes onset across 12 years of life. Overall, this work supports incorporation of islet autoantibody timing, type and titre in risk stratification models for aetiologic studies, prevention trials and disease screening.

Suppression of menstruation and/or ovarian function in adolescent girls may be desired for a variety of reasons. Numerous medical options exist. The choice of the appropriate modality for an individual patient depends on several factors based on differences in the efficacy of achieving menstrual suppression as well as in their side effect profiles. Adolescence is also a period of bone mass accrual in girls, and several of these modalities may negatively influence peak bone mass. This review focuses on the efficacy of achieving menstrual suppression and the effect on bone health of the various options through an overview of the current literature and also highlights areas in need of further research.

Context Identification of modifiable risk factors, including genetic and acquired disorders of lipid and lipoprotein metabolism, is increasingly recognized as an opportunity to prevent premature cardiovascular disease (CVD) in at-risk youth. Pediatric endocrinologists are at the forefront of this emerging public health concern and can be instrumental in beginning early interventions to prevent premature CVD-related events during adulthood. Aim In this article, we use informative case presentations to provide practical approaches to the management of pediatric dyslipidemia. Cases We present 3 scenarios that are commonly encountered in clinical practice: isolated elevation of low-density lipoprotein cholesterol (LDL-C), combined dyslipidemia, and severe hypertriglyceridemia. Treatment with statin is indicated when the LDL-C is ≥190 mg/dL (4.9 mmol/L) in children ≥10 years of age. For LDL-C levels between 130 and 189 mg/dL (3.4-4.89 mmol/L) despite dietary and lifestyle changes, the presence of additional risk factors and comorbid conditions would favor statin therapy. In the case of combined dyslipidemia, the primary treatment target is LDL-C ≤130 mg/dL (3.4 mmol/L) and the secondary target non-high-density lipoprotein cholesterol 1000 mg/dL (11.3 mmol/L), dietary fat restriction remains the cornerstone of therapy, even though the landscape of medications is changing. Conclusion Gene variants, acquired conditions, or both are responsible for dyslipidemia during childhood. Extreme elevations of triglycerides can lead to pancreatitis. Early identification and management of dyslipidemia and cardiovascular risk factors is extremely important.

Context Pediatric obesity is a serious health problem in the United States. While lifestyle modification therapy with dietary changes and increased physical activity are integral for the prevention and treatment of mild to moderate obesity in youth, only a modest effect on sustained weight reduction is observed in children and young adults with severe obesity. This underscores the need for additional evidence-based interventions for children and adolescents with severe obesity, including pharmacotherapy, before considering invasive procedures such as bariatric surgery. Evidence Acquisition This publication focuses on recent advances in pharmacotherapy of obesity with an emphasis on medications approved for common and rarer monogenic forms of pediatric obesity. Evidence Synthesis We review medications currently available in the United States, both those approved for weight reduction in children and “off-label” medications that have a broad safety margin. Conclusion It is intended that this review will provide guidance for practicing clinicians and will encourage future exploration for successful pharmacotherapy and other interventions for obesity in youth.

* Abbreviations: FDA — : US Food and Drug Administration RCT — : randomized controlled trial T2DM — : type 2 diabetes mellitus Childhood obesity has steadily become a contemporary epidemic with serious public health implications.1 Approximately 70% of children with obesity will remain obese in adulthood.2 Obesity is a risk factor for development of atherosclerosis and type 2 diabetes mellitus (T2DM),3 and its prevention and management represents a priority for pediatric primary care providers. This underscores the need for evidence-based interventions for children and adolescents with obesity, including pharmacotherapy.4 Metformin is US Food and Drug Administration (FDA) approved for use in children 10 years of age and older with T2DM and has been used off label to achieve weight loss in children. In the current issue of Pediatrics , Masarwa et al5 present a systematic review of the safety and efficacy of metformin use from randomized controlled trials (RCTs) in children and adolescents. The authors demonstrated that metformin therapy resulted in modest benefits in reduction of BMI in those with obesity. Among the 14 RCTs in which BMI was reported, metformin was modestly efficacious at decreasing BMI (range of mean changes: −2.70 to 1.30) compared with a placebo (−1.12 to 1.90). As pointed out by the authors, the results across the studies were heterogeneous, with 11 RCTs suggesting that it decreased BMI, whereas 3 RCTs revealed an increase in BMI. Among the 7 RCTs in which a BMI z score was reported, metformin consistently resulted in a decrease … Address correspondence to Vandana Raman, MD, Division of Endocrinology, Department of Pediatrics, University of Utah School of Medicine, 81 N Mario Capecchi Dr, Salt Lake City, UT 84113. E-mail: vana.raman{at}hsc.utah.edu

Prevalence of metabolic syndrome in children and adolescents is increasing, in parallel with the increasing trends in obesity rates. Varying definitions of this syndrome have hindered the development of a consensus for the diagnostic criteria in the pediatric population. While pathogenesis of metabolic syndrome is not completely understood, insulin resistance and subsequent inflammation are thought to be among its main mechanistic underpinnings. Overweight and obesity are cardinal features, along with abnormal glucose metabolism, dyslipidemia, and hypertension. Other disorders associated with metabolic syndrome include fatty liver, polycystic ovarian syndrome (PCOS), and pro-inflammatory states. Prevention and management of this condition can be accomplished with lifestyle modifications, behavioral interventions, pharmacological and surgical interventions as needed.

Insulin delivery via injection and continuous subcutaneous insulin infusion (CSII) via insulin pump were compared in a cross-sectional study (n = 669) and retrospective longitudinal study (n = 1904) of young children (

To examine the current extent of the obesity problem in 2 large pediatric clinical registries in the US and Europe and to examine the hypotheses that increased body mass index (BMI) z-scores (BMIz) are associated with greater hemoglobin A1c (HbA1c) and increased frequency of severe hypoglycemia in youth with type 1 diabetes (T1D).International (World Health Organization) and national (Centers for Disease Control and Prevention/German Health Interview and Examination Survey for Children and Adolescents) BMI references were used to calculate BMIz in participants (age 2-18 years and ≥ 1 year duration of T1D) enrolled in the T1D Exchange (n = 11,435) and the Diabetes Prospective Follow-up (n = 21,501). Associations between BMIz and HbA1c and severe hypoglycemia were assessed.Participants in both registries had median BMI values that were greater than international and their respective national reference values. BMIz was significantly greater in the T1D Exchange vs the Diabetes Prospective Follow-up (P.001). After stratification by age-group, no differences in BMI between registries existed for children 2-5 years, but differences were confirmed for 6- to 9-, 10- to 13-, and 14- to 17-year age groups (all P.001). Greater BMIz were significantly related to greater HbA1c levels and more frequent occurrence of severe hypoglycemia across the registries, although these associations may not be clinically relevant.Excessive weight is a common problem in children with T1D in Germany and Austria and, especially, in the US. Our data suggest that obesity contributes to the challenges in achieving optimal glycemic control in children and adolescents with T1D.

OBJECTIVE Exenatide improves postprandial glycemic excursions in type 2 diabetes. Exenatide could benefit type 1 diabetes as well. We aimed to determine an effective and safe glucose-lowering adjuvant exenatide dose in adolescents with type 1 diabetes. RESEARCH DESIGN AND METHODS Eight subjects completed a three-part double-blinded randomized controlled study of premeal exenatide. Two doses of exenatide (1.25 and 2.5 μg) were compared with insulin monotherapy. Prandial insulin dose was reduced by 20%. Gastric emptying and hormones were analyzed for 300 min postmeal. RESULTS Treatment with both doses of exenatide versus insulin monotherapy significantly reduced glucose excursions over 300 min (P < 0.0001). Exenatide administration failed to suppress glucagon but delayed gastric emptying (P < 0.004). CONCLUSIONS Adjunctive exenatide therapy reduces postprandial hyperglycemia in adolescents with type 1 diabetes. This reduction in glucose excursion occurs despite reduction in insulin dose. We suggest that exenatide has therapeutic potential as adjunctive therapy in type 1 diabetes.

Context Gonadotropin-releasing hormone (GnRH) has been the standard test for diagnosing central precocious puberty. Because GnRH is no longer available, GnRH analogues (GnRHa) are now used. Random LH concentration, measured by the third-generation immunochemiluminometric assay, is a useful screening tool for central precocious puberty. However, GnRHa stimulation test should be considered, when a basal LH measurement is inconclusive. However optimal sampling times for luteinizing hormone (LH) have yet to be established. Purpose To determine the appropriate sampling time for LH post leuprolide challenge. Methods A retrospective analysis of multi-sample GnRHa stimulation tests performed in 155 children (aged 1–9 years) referred for precocious puberty to Texas Children’s Hospital. After 20 mcg/kg of SQ leuprolide acetate, samples were obtained at 0, 1, 3, and 6 hours. Results Of 71 children with clinical evidence of central precocious puberty, fifty nine children had a peak LH >5 mIU/mL. 52 (88%) of these responders had positive responses at 1 hour (95% CI is 80–96%), whereas all 59 children (100%) had a peak LH response >5 mIU/mL at 3 hours (95% CI is 94-100%), P = 0.005. Conclusions A single serum LH sample collected 3 hours post GnRHa challenge is the optimal sample to establish the diagnosis of central precocious puberty.

Insulin administration is the primary therapy for type 1 diabetes mellitus (T1DM). Current available insulin therapies do not successfully enable children with T1DM to reach glycemic goals without side effects such as hypoglycemia and weight gain. Pramlintide is a synthetic analog of human amylin that acts in conjunction with insulin to delay gastric emptying and inhibit the release of glucagon and is indicated for use in patients with type 1 and type 2 diabetes. Recent studies in adult patients have examined the role of glucagon-like peptide 1 (GLP-1) and agents that bind to its receptor in type 1 diabetes. It is hypothesized that a major component of the glycemic effect is attributable to the known action of GLP-1 to delay gastric emptying and to inhibit glucagon secretion. Further studies with the use of amylin analogs and long-acting GLP-1 agonists as congeners with insulin in T1DM are indicated in children. In recent years, our better understanding of the pathophysiology of diabetes has led to the development of new therapies for diabetes. This article reviews the potential use of these newer pharmacologic agents as adjunctive therapy in T1DM in children and adolescents.

Objective To assess the risk factors for developing hyperglycemia and diabetes mellitus (DM) in children with pancreatitis. Study design Patients (from infants to age 21 years) hospitalized with acute pancreatitis (AP), acute recurrent pancreatitis (ARP), and chronic pancreatitis were studied retrospectively. Subjects with known DM or cystic fibrosis before presentation with pancreatitis were excluded. Results A total of 176 patients met the study criteria. Of these, 140 had AP, 29 had ARP, and 7 had chronic pancreatitis. Severe pancreatitis was associated with hyperglycemia; 41% of the patients with hyperglycemia required insulin, and 8 patients (4.5%) developed DM requiring insulin by the time of discharge. These 8 patients with postpancreatitis DM were more likely to be overweight. Five of the 8 patients had a seizure disorder, and 4 had another comorbidity, such as mental retardation or cerebral palsy. Seven of the 8 patients who developed DM had a single episode of AP, and one patient had ARP. Conclusions Our findings indicate that hyperglycemia and DM can occur with pancreatitis. In some cases, postpancreatitis DM was associated with mental retardation, seizure disorder, and use of antiseizure medication. As opposed to adults who develop DM after chronic pancreatitis, children can develop DM due to a single episode of AP.

SPONASTRIME dysplasia is an autosomal-recessive spondyloepimetaphyseal dysplasia characterized by spine (spondylar) abnormalities, midface hypoplasia with a depressed nasal bridge, metaphyseal striations, and disproportionate short stature. Scoliosis, coxa vara, childhood cataracts, short dental roots, and hypogammaglobulinemia have also been reported in this disorder. Although an autosomal-recessive inheritance pattern has been hypothesized, pathogenic variants in a specific gene have not been discovered in individuals with SPONASTRIME dysplasia. Here, we identified bi-allelic variants in TONSL, which encodes the Tonsoku-like DNA repair protein, in nine subjects (from eight families) with SPONASTRIME dysplasia, and four subjects (from three families) with short stature of varied severity and spondylometaphyseal dysplasia with or without immunologic and hematologic abnormalities, but no definitive metaphyseal striations at diagnosis. The finding of early embryonic lethality in a Tonsl-/- murine model and the discovery of reduced length, spinal abnormalities, reduced numbers of neutrophils, and early lethality in a tonsl-/- zebrafish model both support the hypomorphic nature of the identified TONSL variants. Moreover, functional studies revealed increased amounts of spontaneous replication fork stalling and chromosomal aberrations, as well as fewer camptothecin (CPT)-induced RAD51 foci in subject-derived cell lines. Importantly, these cellular defects were rescued upon re-expression of wild-type (WT) TONSL; this rescue is consistent with the hypothesis that hypomorphic TONSL variants are pathogenic. Overall, our studies in humans, mice, zebrafish, and subject-derived cell lines confirm that pathogenic variants in TONSL impair DNA replication and homologous recombination-dependent repair processes, and they lead to a spectrum of skeletal dysplasia phenotypes with numerous extra-skeletal manifestations.