Medication-induced diabetes during induction treatment for ALL, an early marker for future metabolic risk?

Medication-induced diabetes (MID) is seen in children treated for acute lymphoblastic leukemia (ALL) mostly during induction, due to the use of l-asparaginase and glucocorticoids. Our objective was to assess whether MID during induction, is a risk factor for future impaired glucose tolerance (IGT), diabetes, or metabolic syndrome. Ninety survivors of pediatric ALL, ages 10 yr and older were recruited, 30 with history of MID and 60 controls. Waist/height ratio >0.5 was considered as an increased risk for central adiposity and insulin resistance. Lipid profile and an oral glucose tolerance test (OGTT) were performed. Study patients were older than controls (17.2 vs. 14.9, p < 0.05). The groups had similar sex distribution, body mass index (BMI) z-score, and Tanner staging. A waist/height ratio of >0.5 was seen in 60 and 31.7% of the study and control groups, respectively (p = 0.01). Increased frequency of IGT in the study group compared with the control group was seen (13.3 and 1%, respectively) (p = 0.07). We observed a trend toward higher proportion of patients with multiple features of metabolic syndrome in the study compared with control group (16.7 vs. 5%, p = 0.09). In conclusion, MID during induction may be an early marker for metabolic disturbances later in life. The higher rates of increased waist/height ratio, and subjects with multiple metabolic syndrome features, may predict a metabolic risk in children with history of MID. Rates of IGT were four fold higher in the study group although not statistically significant. MID may be a 'red flag' indicating the need for ongoing metabolic screening and lifestyle modifications to prevent future metabolic disease.

Primary osteoporosis without features of OI in children and adolescents: clinical and genetic characteristics.

Our aim was to characterize clinical findings and familial associations, and to examine candidate genes for disease-causing mutations in a cohort of children suffering from primary osteoporosis without features of osteogenesis imperfecta. Patients with osteoporosis and their nuclear families were studied. Medical history was reviewed. Calcium homeostasis parameters were measured and spinal radiographs obtained. BMD was determined by DXA for patients, parents and siblings. LRP5, LRP6, and PTHLH genes were sequenced. Twenty-seven patients (14 males) from 24 families were recruited. Median age at presentation was 10.1 years (range 3.3-15.6 years). One-third of the children had at least one parent with a BMD below the expected range for age. LRP5, LRP6, and PTHLH showed no causative mutations. Four polymorphisms in LRP5 were overrepresented in patients; the minor allele frequency of Q89R, V667M, N740N, and A1330V was significantly higher than in controls. Age of onset, clinical severity, and inheritance patterns are variable in children with primary osteoporosis. Several patients had evidence suggestive of familial transmission. The underlying genetic factors remain to be elucidated.

Medication induced diabetes during induction in pediatric acute lymphoblastic leukemia: prevalence, risk factors and characteristics.

INTRODUCTION: Medication induced diabetes (MID) during induction therapy (MIDi) in patients with acute lymphoblastic leukemia (ALL) is not well characterized in children, with recent studies yielding conflicting results. PURPOSE: The purpose of the study was to describe the prevalence of MIDi and risk factors for its development. METHODS: We retrospectively gathered demographic, disease course and treatment data on 363 patients aged 1 to 17.9 years diagnosed with ALL at a pediatric tertiary care hospital between 1998 and 2005. MIDi was defined as blood glucose ≥200 mg/dL (11.1 mmol/L) on at least 2 separate days during induction. RESULTS: Fifty-seven subjects (15.7%) developed MIDi during the study period. Patients ≥10 years were more likely to develop MIDi than those <10 years (odds ratio [OR] 9.6, 95% confidence interval [CI] 5.1-17.8). BMI percentile among those with MIDi (mean ± SD 58.2 ± 31.0) did not differ from those without MIDi (52.2 ± 32.0, P = 0.429). The presence of Trisomy 21 (OR 3.6, 95% CI 1.1-11.4, P = 0.030) and CNS involvement at diagnosis (OR 3.8, 95% CI 1.4-10.1, P = 0.009) were associated with an increased risk of MIDi. After adjustment for potential confounding variables, age ≥10 years and the presence of CNS disease at diagnosis remained significantly associated with MIDi. CONCLUSIONS: Older age and CNS involvement at diagnosis increase the risk of MIDi. In contrast to previous studies, higher BMI was not associated with MIDi in our population.

Mild infantile hypercalcemia: diagnostic tests and outcomes.

OBJECTIVE: To assess outcome in a cohort of patients with infantile hypercalcemia followed over 3 years. STUDY DESIGN: Patients (n = 32) presenting to the calcium clinic between July 2002 and September 2008 were studied. In addition to tests of calcium phosphate metabolism, serum insulin-like growth factor-1, calcitonin, urine citrate, and calcium-sensing receptor gene analysis were obtained. RESULTS: Mean age at presentation was 6.0 ± 6.3 months. Mean calcium level was 11.4 ± 0.7 mg/dL (2.84 ± 0.17 mmol/L). A recognized cause was found in 14% and a probable cause in 14% of the cohort. Those with nephrocalcinosis (n = 11) had significantly lower mean weight SDS and higher mean calcium levels. The biochemical profile of those in whom no cause could be determined included nonsuppressed parathyroid hormone with either normal or increased 1,25(OH)(2)D. Hypercalcemia resolved in 20 patients. However, in approximately a third, there was persistence in hypercalcemia, hypercalciuria, or nephrocalcinosis. CONCLUSIONS: The addition of 1,25(OH)(2)D and calcium-sensing receptor mutation analysis to a panel of investigations may improve diagnostic yield. Clinical outcome is overall good, however, one-third need ongoing follow-up.

Screening and Treatment Outcomes in Adults and Children With Type 1 Diabetes and Asymptomatic Celiac Disease: The CD-DIET Study.

OBJECTIVE: To describe celiac disease (CD) screening rates and glycemic outcomes of a gluten-free diet (GFD) in patients with type 1 diabetes who are asymptomatic for CD. RESEARCH DESIGN AND METHODS: Asymptomatic patients (8-45 years) were screened for CD. Biopsy-confirmed CD participants were randomized to GFD or gluten-containing diet (GCD) to assess changes in HbA1c and continuous glucose monitoring over 12 months. RESULTS: Adults had higher CD-seropositivity rates than children (6.8% [95% CI 4.9-8.2%, N = 1,298] vs. 4.7% [95% CI 3.4-5.9%, N = 1,089], P = 0.035) with lower rates of prior CD screening (6.9% vs. 44.2%, P < 0.0001). Fifty-one participants were randomized to a GFD (N = 27) or GCD (N = 24). No HbA1c differences were seen between the groups (+0.14%, 1.5 mmol/mol; 95% CI -0.79 to 1.08; P = 0.76), although greater postprandial glucose increases (4-h +1.5 mmol/L; 95% CI 0.4-2.7; P = 0.014) emerged with a GFD. CONCLUSIONS: CD is frequently observed in asymptomatic patients with type 1 diabetes, and clinical vigilance is warranted with initiation of a GFD.

Dead-in-bed syndrome - a diabetes nightmare.

We report in this study the death in bed of a 14-yr-old girl with type 1 diabetes and a review of the existing literature on this topic. Diagnosed at 5 yr of age, the patient followed a relatively benign disease course. Hemoglobin A1c was 6.6-8.4%, and there were no hospital admissions apart from the one at diagnosis. Hypoglycemic episodes were not excessive or severe. At age 14 yr, the patient was found dead in bed after having been well the night before. No apparent explanation could be provided. The 'dead-in-bed' syndrome accounts for 5-6% of mortality cases in patients with type 1 diabetes, amounting to two to six cases per 10 000 patient years. Theories attempting to explain the mechanism for this syndrome include hypoglycemia or cardiac autonomic dysfunction. This case emphasizes several problems faced by clinicians: the risk for sudden death in youth with diabetes, which may compromise good glycemic control, the question of early detection of autonomic dysfunction, and the need to understand this phenomenon better and search for preventive measures.

A case of Jatropha multifida poisoning resembling organophosphate intoxication.

Four siblings presented with vomiting, diarrhea and miosis following ingestion of the plant. This is the first report of miosis as a presenting sign of Jatropha intoxication. The combination of vomiting, diarrhea and miosis resembles the clinical presentation of organophosphate poisoning. This fact warrants the consideration of Jatropha ingestion in the differential diagnosis of organophosphate ingestion. Treatment of Jatropha intoxication is supportive with emphasis on rehydration. Measurement of plasma acetylcholinesterase activity levels, which is normal after Jatropha ingestion and decreased following organophosphate poisoning, may help differentiate between the two.

Pediatric thyroid nodules: ultrasonographic characteristics and inter-observer variability in prediction of malignancy.

BACKGROUND: Pediatric thyroid nodules, while uncommon, have high malignancy risk. The objectives of the study were (1) to identify sonographic features predictive of malignancy; (2) to create a prediction model; and (3) to assess inter-observer agreement among radiologists. METHODS: All available cases of thyroid nodules, surgically removed between 2000 and 2009. Three radiologists reviewed the sonographic images; 2 pathologists reviewed the tissue specimens. Adult prediction models were applied. Interobserver variability was assessed. RESULTS: Twenty-seven subjects, mean age 13.1±3.4 years, were included. Nineteen nodules were differentiated thyroid carcinomas. On multivariate analysis, size was the only significant predictor of malignancy. On recursive partitioning analysis, size >35 mm with microcalcification and ill-defined margins yielded the best prediction model. Radiologist inter-observer agreement regarding malignancy was moderate (κ=0.50). CONCLUSIONS: Larger size, microcalcifications and ill-defined margins on ultrasound demonstrate the best predictive model for malignancy in the pediatric population. Experienced pediatric radiologists demonstrate moderate inter-observer agreement in prediction of malignancy.

The Celiac Disease and Diabetes-Dietary Intervention and Evaluation Trial (CD-DIET) protocol: a randomised controlled study to evaluate treatment of asymptomatic coeliac disease in type 1 diabetes.

INTRODUCTION: Coeliac disease (CD) is an autoimmune condition characterised by gluten-induced intestinal inflammation, and observed at a 5-10 fold greater prevalence in type 1 diabetes. While universal screening for CD in patients with diabetes is frequently advocated, objective data is limited as to benefits on diabetes control, bone health or quality of life related to the adoption of a gluten-free diet (GFD) in the large proportion of patients with diabetes with asymptomatic CD. The Celiac Disease and Diabetes-Dietary Intervention and Evaluation Trial (CD-DIET) study is a multicenter, randomised controlled trial to evaluate the efficacy and safety of a GFD in patients with type 1 diabetes with asymptomatic CD. METHODS AND ANALYSIS: Children and adults (8-45 years) with type 1 diabetes will be screened for asymptomatic CD. Eligible patients with biopsy-proven CD will be randomly assigned in a 1:1 ratio to treatment with a GFD for 1 year, or continue with a gluten-containing diet. The primary outcome will evaluate the impact of the GFD on change in glycated haemoglobin. Secondary outcomes will evaluate changes in bone mineral density, blood glucose variability and health-related quality of life between GFD-treated and the regular diet group over a 1-year period. The study was initiated in 2012 and has subsequently expanded to multiple paediatric and adult centres in Ontario, Canada. ETHICS AND DISSEMINATION: The findings from this study will provide high-quality evidence as to the impact of GFD treatment on glycaemic control and complications in asymptomatic children and adults with CD and type 1 diabetes. TRIAL REGISTRATION NUMBER: NCT01566110.

A child with autoimmune polyendocrinopathy candidiasis and ectodermal dysplasia treated with immunosuppression: a case report.

INTRODUCTION: Common features of autoimmune polyendocrinopathy-candidiasis-ectodermal dysplasia include candidiasis, hypoparathyroidism and hypoadrenalism. The initial manifestation of autoimmune polyendocrinopathy-candidiasis-ectodermal dysplasia may be autoimmune hepatitis, keratoconjunctivitis, frequent fever with or without a rash, chronic diarrhea, or different combinations of these with or without oral candidiasis. CASE PRESENTATION: We discuss a profoundly affected 2.9-year-old Caucasian girl of Western European descent with a dramatic response to immunosuppression (initially azathioprine and oral steroids, and then subsequently mycophenolate mofetil monotherapy). At four years of follow-up, her response to mycophenolate mofetil is excellent. CONCLUSION: The clinical features of autoimmune polyendocrinopathy-candidiasis-ectodermal dysplasia may continue for years before some of the more common components appear. In such cases, it may be life-saving to diagnose autoimmune polyendocrinopathy-candidiasis-ectodermal dysplasia and commence therapy with immunosuppressive agents. The response of our patient to immunosuppression with mycophenolate mofetil has been dramatic. It is possible that other patients with this condition might also benefit from immunosuppression.