The impact of type 1 diabetes mellitus in childhood on academic performance: A matched population-based cohort study.

BACKGROUND AND OBJECTIVE: The impact of type 1 diabetes mellitus (T1D) on academic performance is inconclusive. This study aims to compare scholastic performance and high-school completion in young people hospitalized with T1D compared to matched peers not hospitalized with diabetes. RESEARCH DESIGN: Retrospective case-comparison cohort study. METHOD: A population-level matched case-comparison study of people aged ≤18 hospitalized with T1D during 2005-2018 in New South Wales, Australia using linked health-related and education records. The comparison cohort was matched on age, gender, and residential postcode. Generalized linear mixed modeling examined risk of school performance below the national minimum standard (NMS) and generalized linear regression examined risk of not completing high school for young people hospitalized with T1D compared to peers. Adjusted relative risks (ARR) were calculated. RESULTS: Young females and males hospitalized with T1D did not have a higher risk of not achieving the NMS compared to peers for numeracy (ARR: 1.19; 95%CI 0.77-1.84 and ARR: 0.74; 95%CI 0.46-1.19) or reading (ARR: 0.98; 95%CI 0.63-1.50 and ARR: 0.85; 95%CI 0.58-1.24), respectively. Young T1D hospitalized females had a higher risk of not completing year 11 (ARR: 1.73; 95%CI 1.19-2.53) or 12 (ARR: 1.65; 95%CI 1.17-2.33) compared to peers, while hospitalized T1D males did not. CONCLUSIONS: There was no difference in academic performance in youth hospitalized with T1D compared to peers. Improved glucose control and T1D management may explain the absence of school performance decrements in students with T1D. However, females hospitalized with T1D had a higher risk of not completing high school. Potential associations of this increased risk, with attention to T1D and psycho-social management, should be investigated.

Global consensus on nutritional rickets: Implications for Australia.

In 2016, a global consensus on the prevention, diagnosis and management of nutritional rickets was published. The bone and mineral working group of the Australasian Paediatric Endocrine Group provides a summary and highlights differences to previous Australian and New Zealand (ANZ) guidelines on vitamin D deficiency and their implications for clinicians. Key points are: (i) The International Consensus document is focused on nutritional rickets, whereas the ANZ guidelines were focused on vitamin D deficiency. (ii) Definitions for the interpretation of 25-hydroxy vitamin D (25OHD) levels do not differ between statements. (iii) The global consensus recommends that routine 25OHD screening should not be performed in healthy children and recommendations for vitamin D supplementation are not based solely on 25OHD levels. The Australasian Paediatric Endocrine Group bone and mineral working group supports that screening for vitamin D deficiency should be restricted to populations at risk. (iv) Recommendations from the global consensus for vitamin D dosages for the therapy of nutritional rickets (diagnosed based on history, physical examination, biochemical testing and a confirmation by X-rays) are higher than in ANZ publications. (v) The global consensus recommends the implementation of public health strategies such as universal supplementation with vitamin D from birth to 1 year of age and food fortification. We conclude that updated global recommendations for therapy of nutritional rickets complement previously published position statements for Australia and New Zealand. Screening, management and the implementation of public health strategies need to be further explored for Australia.

Sydney Diabetes centre's experience of the Australian Government's roll out of subsidised continuous glucose monitoring for children with type 1 diabetes mellitus.

AIM: To determine patient/carer expectations of continuous glucose monitoring (CGM) and short-term satisfaction, to assess the efficacy of CGM in improving: fear of hypoglycaemia and glycaemic control (HbA1c , ketosis, hypoglycaemia) and to determine time requirements of diabetes clinic staff in commencing and administering CGM. METHODS: We assessed CGM-naïve patients starting on CGM at a Sydney Diabetes Centre following the introduction of a nationwide government subsidy for CGM. A standardised questionnaire was administered collecting demographic and glycaemic information in addition to Likert scale assessment of expectations and satisfaction. Clinic staff reported time dedicated to CGM education, commencement and follow-up. RESULTS: A total of 55 patients or parents/carers completed baseline questionnaires, with 37 completing a 3-month follow-up questionnaire. There were high expectations of CGM prior to commencement and high satisfaction ratings on follow-up. CGM improved fear of hypoglycaemia, and total daily insulin dose increased after commencement of CGM. There was a trend towards lower HbA1c that was not statistically significant and no statistically significant reduction in ketosis or hypoglycaemia. Comments were mostly positive, with some concern raised regarding technical issues and a lack of subsidy after 21 years of age. Staff time requirements were substantial, with an estimated average of 7.7 h per patient per year. CONCLUSIONS: Patients and families have high expectations of CGM, and satisfaction levels are high in the short term. Total insulin delivery increased after CGM commencement. Time requirements by staff are substantial but are worthwhile if families' overall satisfaction levels are high.

Consensus guidelines on the use of bisphosphonate therapy in children and adolescents.

Bisphosphonate therapy is the mainstay of pharmacological intervention in young people with skeletal fragility. The evidence of its use in a variety of conditions remains limited despite over three decades of clinical experience. On behalf of the Australasian Paediatric Endocrine Group, this evidence-based consensus guideline presents recommendations and discusses the graded evidence (using the GRADE system) for these recommendations. Primary bone fragility disorders such as osteogenesis imperfecta are considered separately from osteoporosis secondary to other clinical conditions (such as cerebral palsy, Duchenne muscular dystrophy). The use of bisphosphonates in non-fragility conditions, such as fibrous dysplasia, avascular necrosis, bone cysts and hypercalcaemia, is also discussed. While these guidelines provide an evidence-based approach where possible, further research is required in all clinical applications in order to strengthen the recommendations made.

Fracture in Duchenne Muscular Dystrophy: Natural History and Vitamin D Deficiency.

The present study examined the natural history of fracture and vitamin D levels in Duchenne muscular dystrophy patients, who are vulnerable to osteoporosis and fractures. Retrospective analysis of a cohort of 48 Duchenne muscular dystrophy patients revealed that 43% of patients experienced ≥1 fracture. Fracture probabilities at ages 6, 9, 12, and 15 years were 4%, 9%, 31%, and 60% respectively, accelerating around the time of ambulation loss (mean age 11.8 ± 2.7 years). Chronic corticosteroid therapy was utilized in 69% of patients and was associated with all vertebral fractures. A history of vitamin D deficiency occurred in 84%, and 35% were currently deficient. Despite chronic vitamin D supplementation, 38% remained deficient. These results demonstrate that osteoporosis and fracture remain major concerns in Duchenne muscular dystrophy. Bone health should be optimized well before loss of ambulation, however current levels of vitamin D supplementation may be inadequate given high levels of deficiency.

Clinical Guidelines for Management of Bone Health in Rett Syndrome Based on Expert Consensus and Available Evidence.

OBJECTIVES: We developed clinical guidelines for the management of bone health in Rett syndrome through evidence review and the consensus of an expert panel of clinicians. METHODS: An initial guidelines draft was created which included statements based upon literature review and 11 open-ended questions where literature was lacking. The international expert panel reviewed the draft online using a 2-stage Delphi process to reach consensus agreement. Items describe the clinical assessment of bone health, bone mineral density assessment and technique, and pharmacological and non-pharmacological interventions. RESULTS: Agreement was reached on 39 statements which were formulated from 41 statements and 11 questions. When assessing bone health in Rett syndrome a comprehensive assessment of fracture history, mutation type, prescribed medication, pubertal development, mobility level, dietary intake and biochemical bone markers is recommended. A baseline densitometry assessment should be performed with accommodations made for size, with the frequency of surveillance determined according to individual risk. Lateral spine x-rays are also suggested. Increasing physical activity and initiating calcium and vitamin D supplementation when low are the first approaches to optimizing bone health in Rett syndrome. If individuals with Rett syndrome meet the ISCD criterion for osteoporosis in children, the use of bisphosphonates is recommended. CONCLUSION: A clinically significant history of fracture in combination with low bone densitometry findings is necessary for a diagnosis of osteoporosis. These evidence and consensus-based guidelines have the potential to improve bone health in those with Rett syndrome, reduce the frequency of fractures, and stimulate further research that aims to ameliorate the impacts of this serious comorbidity.

Single High-Dose Oral Vitamin D3 Therapy (Stoss): A Solution to Vitamin D Deficiency in Children With Inflammatory Bowel Disease?

OBJECTIVES: Vitamin D deficiency is common in children with inflammatory bowel disease (IBD). The aim of this study was to determine the safety and efficacy of stoss therapy on vitamin D levels during a period of 6 months in children with IBD and vitamin D deficiency (<50 nmol/L). METHODS: A retrospective chart review was undertaken, focusing upon children managed in the IBD clinic at Sydney Children's Hospital between 2006 and 2010. Those with a 25-hydroxyvitamin D (25-OHD) level <50 nmol/L and those who received stoss therapy were included in this study. RESULTS: A total of 76 children received stoss therapy. There was a significant and sustained increase in 25-OHD levels at all of the time points compared with baseline (40.8 ±â€Š7.5 nmol/L), 1 month (145.6 ±â€Š51.8 nmol/L), 3 months (87.1 ±â€Š28.4 nmol/L), and 6 months 69.2 ±â€Š31.3 nmol/L). There were no significant changes in serum calcium, phosphate, or parathyroid hormone at any time points. CONCLUSIONS: Stoss therapy safely and effectively achieved and maintained a level of 25-OHD >50 nmol/L during 6 months in these children with IBD. Further prospective studies are now required to confirm this finding and establish whether this intervention has other benefits.

Longitudinal bone mineral content and density in Rett syndrome and their contributing factors.

Bone mass and density are low in females with Rett syndrome. This study used Dual energy x-ray absorptiometry to measure annual changes in z-scores for areal bone mineral density (aBMD) and bone mineral content (BMC) in the lumbar spine and total body in an Australian Rett syndrome cohort at baseline and then after three to four years. Bone mineral apparent density (BMAD) was calculated in the lumbar spine. Annual changes in lean tissue mass (LTM) and bone area (BA) were also assessed. The effects of age, genotype, mobility, menstrual status and epilepsy diagnosis on these parameters were also investigated. The baseline sample included 97 individuals who were representative of the total live Australian Rett syndrome population under 30years in 2005 (n=274). Of these 74 had a follow-up scan. Less than a quarter of females were able to walk on their own at follow-up. Bone area and LTM z-scores declined over the time between the baseline and follow-up scans. Mean height-standardised z-scores for the bone outcomes were obtained from multiple regression models. The lumbar spine showed a positive mean annual BMAD z-score change (0.08) and a marginal decrease in aBMD (-0.04). The mean z-score change per annum for those 'who could walk unaided' was more positive for LS BMAD (p=0.040). Total body BMD mean annual z-score change from baseline to follow-up was negative (-0.03). However this change was positive in those who had achieved menses prior to the study (0.03, p=0,040). Total body BMC showed the most negative change (-0.60), representing a decrease in bone mineral content over time. This normalised to a z-score change of 0.21 once adjusted for the reduced lean tissue mass mean z-score change (-0.21) and bone area mean z-score change (-0.14). Overall, the bone mineral content, bone mineral density, bone area and lean tissue mass z-scores for all outcome measures declined, with the TB BMC showing significant decreases. Weight, height and muscle mass appear to have impacts on bone formation and we recommend that nutritional intake should be closely monitored and a physical activity plan developed to optimise bone health. Pubertal progression should also be assessed in conjunction with serial densitometry assessments to track bone mass and density changes over time.

A pilot randomized controlled trial of a post-discharge program to support emerging adults with type 1 diabetes mellitus transition from pediatric to adult care.

AIMS: There is a paucity of randomized controlled trials (RCT) examining transition from pediatric to adult care in type 1 diabetes mellitus (T1DM). This study aimed to determine if transition in T1DM is more effective with a comprehensive transition program (CTP) compared with standard clinical practice (SCP). METHODS: This RCT recruited as young people left pediatric diabetes services. The trial co-ordinator provided CTP participants with standardized telephone communication support at week 1, and 3, 6, and 12 months post-discharge from pediatric care. SCP participants were briefly contacted at 6 and 12 months post-discharge to confirm transfer status; they received no other post-discharge contact as per usual practice. At 12 months, the primary outcomes were engagement and retention in the adult service and secondary outcomes included hemoglobin A1c (HbA1c), diabetes-related hospitalizations, microvascular complication appearance, and global self-worth. RESULTS: Most CTP participants (11/14) and all SCP (12/12) participants (P = 0.2) transferred to an adult diabetes service; the median time to transfer was 14-15 wk. Overall, participants' frequency of adult diabetes service visits was sub-optimal but their retention in adult care was high. The only group difference was a higher HbA1c at baseline and follow-up in the CTP group. However, a general linear model found that follow-up HbA1c increased by 1.2% for each percentage increase in baseline HbA1c [95% confidence interval (0.4, 1.9; P = 0.01)], independent of treatment group. CONCLUSIONS: Despite the challenges in recruiting adequate numbers, these findings provide valuable insights for future T1DM transition RCTs that are needed to build a more solid evidence-base in this field.

Improved insulin sensitivity and body composition, irrespective of macronutrient intake, after a 12 month intervention in adolescents with pre-diabetes; RESIST a randomised control trial.

BACKGROUND: A higher protein to carbohydrate ratio in the diet may potentiate weight loss, improve body composition and cardiometabolic risk, including glucose homeostasis in adults. The aim of this randomised control trial was to determine the efficacy of two structured lifestyle interventions, differing in dietary macronutrient content, on insulin sensitivity and body composition in adolescents. We hypothesised that a moderate-carbohydrate (40-45% of energy), increased-protein (25-30%) diet would be more effective than a high-carbohydrate diet (55-60%), moderate-protein (15%) diet in improving outcomes in obese, insulin resistant adolescents. METHODS: Obese 10-17 year olds with either pre-diabetes and/or clinical features of insulin resistance were recruited at two hospitals in Sydney, Australia. At baseline adolescents were prescribed metformin and randomised to one of two energy restricted diets. The intervention included regular contact with the dietician and a supervised physical activity program. Outcomes included insulin sensitivity index measured by an oral glucose tolerance test and body composition measured by dual-energy x-ray absorptiometry at 12 months. RESULTS: Of the 111 adolescents recruited, 85 (77%) completed the intervention. BMI expressed as a percentage of the 95th percentile decreased by 6.8% [95% CI: -8.8 to -4.9], ISI increased by 0.2 [95% CI: 0.06 to 0.39] and percent body fat decreased by 2.4% [95% CI: -3.4 to -1.3]. There were no significant differences in outcomes between diet groups at any time. CONCLUSION: When treated with metformin and an exercise program, a structured, reduced energy diet, which is either high-carbohydrate or moderate-carbohydrate with increased-protein, can achieve clinically significant improvements in obese adolescents at risk of type 2 diabetes. TRIAL REGISTRATION: Australian New Zealand Clinical Trail Registry ACTRN12608000416392 . Registered 25 August 2008.

Population-based incidence of diabetes in Australian youth aged 10-18 yr: increase in type 1 diabetes but not type 2 diabetes.

BACKGROUND: Global incidence of childhood type 2 diabetes has increased, with a greater rise amongst certain ethnic groups. OBJECTIVES: To examine the change in the incidence of type 1 and type 2 diabetes in Australian youth, aged 10-18 yr, in New South Wales, Australia. METHODS: Prospective population-based incidence study (2001-2008). Primary case ascertainment was from the Australasian Paediatric Endocrine Group Diabetes Register, secondary independent ascertainment from the National Diabetes Register. RESULTS: There were 202 incident cases of type 2 diabetes (96 boys, 48%). The mean age at diagnosis (±SD) was 14.6 ± 2.5 yr; 93% were overweight (International Obesity Taskforce Grade ≥1). Mean HbA1c was 8.8 ± 2.8%. Ethnicity was Caucasian 31%, Indigenous Australian 20%, Southeast Asian 11%, North African/Middle Eastern 9%, and NewZealander/Melanesian/Polynesian 8%. The mean annual incidence of type 2 diabetes was 3.0 per 100 000 per year (95% confidence interval (CI): 2.6-3.4) and did not change over time. The mean annual incidence of type 1 diabetes was 22.0 per 100 000 per year (95% CI: 20.8-23.1), and increased by 3.8% per year [incidence rate ratio IRR: 1.04, 95% CI: 1.02-1.06, p = 0.001]. Incidence was higher in Indigenous vs. non-Indigenous youth, IRR: 6.9 (95% CI: 4.7-10.2, p < 0.001). CONCLUSION: In 10-18 yr old youth, in Australia, the incidence of type 2 diabetes has remained steady during the last decade; however, the incidence of type 1 diabetes continues to rise. Most common diabetes in Australian youth is type 1 diabetes.

Optimal macronutrient content of the diet for adolescents with prediabetes; RESIST a randomised control trial.

CONTEXT: Prediabetes and clinical insulin resistance in adolescents are rapidly emerging clinical problems with serious health outcomes. OBJECTIVE: The objective of this study was to determine the efficacy of 2 structured lifestyle interventions, both differing in diet macronutrient composition, on insulin sensitivity. DESIGN: This study was a randomized controlled trial, known as Researching Effective Strategies to Improve Insulin Sensitivity in Children and Teenagers, in 2 hospitals in Sydney, Australia. PARTICIPANTS: Participants included overweight or obese 10- to 17-year-olds with either prediabetes and/or clinical features of insulin resistance. INTERVENTION: At baseline adolescents were prescribed metformin and randomized to a structured diet, which was either high carbohydrate or moderate carbohydrate with increased protein. The program commenced with a 3-month dietary intervention, with the addition of an exercise intervention in the next 3 months. OUTCOMES: The outcomes included an insulin sensitivity, anthropometry, and cardiometabolic profile at 6 months. RESULTS: One hundred eleven subjects (66 girls) were recruited and 98 subjects (58 girls) completed the 6-month intervention. After 3 months the mean insulin sensitivity index increased by 0.3 [95% confidence interval (CI) 0.2-0.4]. After 6 months the mean insulin (picomoles per liter) to glucose ratio (millimoles per liter) decreased by 7.2 [95%CI -12.0 to -2.3], body mass index, expressed as a percentage of the 95th centile, decreased by 9% (95% CI -3 to -15), but there was no significant change in the lipids. There were no significant differences in outcomes between the diet groups at any time point. CONCLUSIONS: These results are in contrast with our hypothesis that adolescents randomized to the increased protein diet would have better outcomes. Further strategies are required to better address prediabetes and clinical features of insulin resistance in adolescents.

Pubertal trajectory in females with Rett syndrome: a population-based study.

BACKGROUND: Rett syndrome is a severe genetic neurodevelopmental disorder mainly affecting females. The aim of this study was to describe pubertal development in a population-based cohort of females with Rett syndrome. METHODS: To assess pubertal trajectory we used six waves of data provided by parents of girls and women, recruited through the Australian population-based Rett Syndrome Database. The age at which adrenarche, thelarche or menarche occurred was used as the parameter for time to event (survival) analysis. The relationships between BMI, mutation type and the trajectories were investigated, using Cox proportional hazards. RESULTS: One quarter of girls reached adrenarche by 9.6 years, half by 11 years and three quarters by 12.6 years. Half reached menarche by 14 years (range 8-23). Being underweight was associated with later age at adrenarche, thelarche and menarche, while higher BMI (overweight) was associated with earlier onset. In general, girls with C-terminal deletions and early truncating mutations reached pubertal stages earlier and those with the p.R168X mutation reached them later. CONCLUSION: The pubertal course in Rett syndrome may be abnormal, sometimes with early adrenarche but delayed menarche. These features may be genotype dependent and may have varying relationships with growth and bone acquisition.

Home blood sodium monitoring, sliding-scale fluid prescription and subcutaneous DDAVP for infantile diabetes insipidus with impaired thirst mechanism.

BACKGROUND/AIMS: Infants with diabetes insipidus (DI), especially those with impaired thirst mechanism or hypothalamic hyperphagia, are prone to severe sodium fluctuations, often requiring hospitalization. We aimed to avoid dangerous fluctuations in serum sodium and improve parental independence. METHODS: A 16-month old girl with central DI, absent thirst mechanism and hyperphagia following surgery for hypothalamic astrocytoma had erratic absorption of oral DDAVP during chemotherapy cycles. She required prolonged hospitalizations for hypernatremia and hyponatremic seizure. Intensive monitoring of fluid balance, weight and clinical assessment of hydration were not helpful in predicting serum sodium. Discharge home was deemed unsafe. Oral DDAVP was switched to subcutaneous (twice-daily injections, starting with 0.01mcg/dose, increasing to 0.024mcg/dose). The parents adjusted daily fluid allocation by sliding-scale, according to the blood sodium level (measured by handheld i-STAT analyser, Abbott). We adjusted the DDAVP dose if fluid allocation differed from maintenance requirements for 3 consecutive days. RESULTS: After 2.5 months, sodium was better controlled, with 84% of levels within reference range (135-145 mmol/L) vs. only 51% on the old regimen (p = 0.0001). The sodium ranged from 132-154 mmol/L, compared to 120-156 on the old regimen. She was discharged home. CONCLUSION: This practical regimen improved sodium control, parental independence, and allowed discharge home.

Homozygous thyroid hormone receptor ß-gene mutations in resistance to thyroid hormone: three new cases and review of the literature.

CONTEXT: The most common cause of resistance to thyroid hormone (RTH) is heterozygous thyroid hormone receptor ß (THRB) gene mutations. Homozygous mutations in the THRB gene are a rare event. OBJECTIVE: In this study, the clinical findings of three new patients (belonging to two families) homozygous for mutations in the THRB gene are compared to three other families in which affected individuals lack a normal TRß. METHODS: We conducted clinical studies and genetic analyses. RESULTS: The clinical presentation in all three homozygous subjects was unusually severe; their phenotype was characterized by compromised intellectual development, tachycardia, goiter, growth retardation, and hearing loss. This was comparable with one other reported patient homozygous for mutant TRß, but not in RTH due to THRB gene deletions. CONCLUSION: We report three new subjects, from two families, in whom RTH was associated with homozygous mutations in the THRB gene. They represent an important addition to the single known patient homozygous for a mutant TRß. The clinical and laboratory abnormalities indicate a strong dominant-negative effect and are in agreement with data obtained from mice expressing a mutant Thrb in both alleles. This report strengthens the concept that the mutated TRß interferes with the function of the TRα1 in humans.

Once daily insulin detemir in cystic fibrosis with insulin deficiency.

The aim of this study was to determine if once daily insulin detemir reverses decline in weight and lung function in patients with cystic fibrosis (CF). 12 patients with early insulin deficiency and six with CF related diabetes (aged 7.2-18.1 years) were treated for a median of 0.8 years. Changes in weight and lung function following treatment were compared to pretreatment changes. Before treatment, the change in weight SD score (ΔWtSDS), percentage of predicted forced expiratory volume in 1 s (Δ%FEV(1)) and percentage of predicted forced vital capacity (Δ%FVC) declined in the whole study population (-0.45±0.38, -7.9±12.8%, -5.8±14.3%) and in the subgroup with early insulin deficiency (-0.41±0.43, -9.8±9.3%, -6.8±10.3%). Following treatment with insulin ΔWtSDS, Δ%FEV(1) and Δ%FVC significantly improved in the whole study population (+0.18±0.29 SDS, p=0.0001; +3.7±10.6%, p=0.007; +5.2±12.7%, p=0.013) and in patients with early insulin deficiency (+0.22±0.31 SDS, p=0.003; +5.3±11.5%, p=0.004; +5.8±13.4%, p=0.024). Randomised controlled trials are now needed.

Increased detection of cystic-fibrosis-related diabetes in Australia.

OBJECTIVES: To estimate the incidence of cystic-fibrosis-related diabetes (CFRD) in youth from New South Wales (NSW) and the Australian Capital Territory (ACT), Australia and to examine demographic/clinical features at diagnosis. METHODS: Incident cases of CFRD in young people aged ≤ 18 years diagnosed during 2000 to 2008 were identified from four paediatric cystic fibrosis (CF) clinics and the NSW/ACT Australasian Paediatric Endocrine Group Diabetes Register. RESULTS: CFRD was diagnosed in 41 cases (59% girls). The estimated mean annual incidence of CFRD among patients with CF was 9.4 per 1000 person years (95% CI 6.8 to 12.8). Incidence increased from 2.0 per 1000 person years in 2000 to 22.1 per 1000 in 2008 (incidence RR 1.3, 95% CI 1.1 to 1.4). Haemoglobin A1c (HbA1c) was abnormal in the majority at diagnosis: median HbA1c was 6.9% (6.2-8.1%). More cases were diagnosed using an oral glucose tolerance test in 2007-2008 compared with previous years (61% vs 6%, p<0.001). CONCLUSIONS: CFRD is increasingly recognised and now affects approximately one in five young people with CF. The rising incidence is likely to be due to increased detection, resulting from greater awareness and changes in screening practices. Widespread uptake of consensus guidelines for screening will ensure accurate case detection, but will also impact on patient care and resource allocation.

Persistently autoantibody negative (PAN) type 1 diabetes mellitus in children.

BACKGROUND: Autoantibody-negative children diagnosed with type 1 diabetes might have unrecognized monogenic or type 2 diabetes. RESEARCH DESIGN AND METHODS: At diagnosis of type 1 diabetes (between ages 0.5 and 16.3 yr, n = 470), autoantibodies [glutamic acid decarboxylase (GAD), insulinoma-associated protein 2 (IA2), insulin autoantibodies (IAA), and/or islet cell antibody (ICA)] were positive (ab+) in 330 and negative in 37 (unknown in 103). Autoantibody-negative patients were retested at median diabetes duration of 3.2 yr (range 0.9-16.2) for autoantibodies (GAD, IA2, ZnT8), human leukocyte antigen (HLA) typing, non-fasting C-peptide, and sequencing of HNF4A, HNF1A, KCNJ11, and INS. RESULTS: Nineteen (5% of 367) remained persistently autoantibody negative (PAN), 17 were positive on repeat testing (PORT), and 1 refused retesting. No mutations were found in PORT. One PAN was heterozygous for P112L mutation in HNF1A and transferred from insulin to oral gliclazide. Another PAN transferred to metformin and the diagnosis was revised to type 2 diabetes. The remaining 17 PAN were indistinguishable from the ab+ group by clinical characteristics. HLA genotype was at high risk for type 1 diabetes in 82% of remaining PAN and 100% of PORT. After excluding patients with diabetes duration <1 yr, C-peptide was detectable more frequently in the remaining PAN (7/16) and PORT (6/17) than in a random selection of ab+ (3/28, p = 0.03). CONCLUSIONS: The diagnosis of type 1 diabetes should be reevaluated in PAN patients, because a subset has monogenic or type 2 diabetes. The remaining PAN have relatively preserved C-peptide compared with ab+, suggesting slower ß-cell destruction, but a very high frequency of diabetogenic HLA, implying that type 1B (idiopathic) diabetes is rare.

Vitamin D deficiency in children with inflammatory bowel disease.

BACKGROUND: Osteopenia and osteoporosis are commonly seen in inflammatory bowel disease (IBD). Vitamin D deficiency potentially contributes to diminished bone acquisition in childhood. OBJECTIVES: The objectives of this study were to assess vitamin D in a group of Australian children with IBD and to ascertain associations between vitamin D status and key clinical factors, for example disease location and severity. METHODS: Data were obtained retrospectively from the records of children with IBD who had at least one measurement of serum 25-hydroxyvitamin D (25(OH)D) over a two-year period. Demographic variables, disease activity, inflammatory markers, disease location, duration, and therapy were recorded. Moderate and severe deficiency were defined as 25(OH)D <51 nmol/l and <30 nmol/l, respectively. Insufficiency was defined as 25(OH)D between 51 and 75 nmol/l. RESULTS: Overall, the mean 25(OH)D level in 78 children (104 measurements) was 71.2 (SD ± 26.5) nmol/l. Fifteen (19%) children were vitamin D deficient and 30 (38%) children were insufficient. Levels of 25(OH)D were not associated with disease location or use of immunosuppressive drugs. Children with vitamin D deficiency had greater corticosteroid exposure than those with normal status (P = 0.001). The mean 25(OH)D of 38 children treated with nutritional therapy at diagnosis was higher than for 17 children initially treated with corticosteroids (P = 0.04). CONCLUSIONS: A high proportion of these Australian children with IBD were vitamin D deficient. This emphasizes the importance of monitoring vitamin D status, and treating deficiency, in the management of pediatric IBD. The possible benefit of nutritional therapy in protection against vitamin D deficiency requires further prospective study.