Whole-exome sequencing for mutation detection in pediatric disorders of insulin secretion: Maturity onset diabetes of the young and congenital hyperinsulinism.

BACKGROUND: To assess the utility of whole-exome sequencing (WES) for mutation detection in maturity-onset diabetes of the young (MODY) and congenital hyperinsulinism (CHI). MODY and CHI are the two commonest monogenic disorders of glucose-regulated insulin secretion in childhood, with 13 causative genes known for MODY and 10 causative genes identified for CHI. The large number of potential genes makes comprehensive screening using traditional methods expensive and time-consuming. METHODS: Ten subjects with MODY and five with CHI with known mutations underwent WES using two different exome capture kits (Nimblegen SeqCap EZ Human v3.0 Exome Enrichment Kit, Nextera Rapid Capture Exome Kit). Analysis was blinded to previously identified mutations, and included assessment for large deletions. The target capture of five exome capture technologies was also analyzed using sequencing data from >2800 unrelated samples. RESULTS: Four of five MODY mutations were identified using Nimblegen (including a large deletion in HNF1B). Although targeted, one mutation (in INS) had insufficient coverage for detection. Eleven of eleven mutations (six MODY, five CHI) were identified using Nextera Rapid (including the previously missed mutation). On reconciliation, all mutations concorded with previous data and no additional variants in MODY genes were detected. There were marked differences in the performance of the capture technologies. CONCLUSIONS: WES can be useful for screening for MODY/CHI mutations, detecting both point mutations and large deletions. However, capture technologies require careful selection.

Oral glucose tolerance test in children and adolescents: positives and pitfalls.

OBJECTIVES: To describe the glycaemic status (assessed by an oral glucose tolerance test (OGTT)) and associated comorbidities in a cohort of Australian children and adolescents at risk of insulin resistance and impaired glucose homeostasis (IGH). METHODS: Twenty-one children and adolescents (three male, 18 female) (18 Caucasian, one Indigenous, two Asian) (20 obese, one lipodystrophy) referred to the Paediatric Endocrinology and Diabetes Clinic underwent a 2-h OGTT with plasma glucose and insulin measured at baseline, + 60 and + 120 min. If abnormal, the OGTT was repeated. RESULTS: The mean (SD) age was 14.2 (1.6) years, BMI 38.8 (7.0) kg/m2 and BMI-SDS 3.6 (0.6). Fourteen patients had fasting insulin levels >21 mU/L. Type 2 diabetes mellitus was diagnosed in one patient, impaired glucose tolerance (IGT) in four patients and impaired fasting glycaemia (IFG) in one patient. Despite no weight loss, only one patient had a persistently abnormal OGTT on repeat testing. Three patients with IGH were medicated with risperidone at the time of the initial OGTT. One patient who had persistent IGT had continued risperidone. The other two patients had initial OGTT results of IGT and diabetes mellitus type 2. They both ceased risperidone between tests and repeat OGTT showed normal glycaemic status. CONCLUSIONS: Use of fasting glucose alone may miss cases of IGH. Diagnosis of IGT should not be made on one test alone. Interpretation of glucose and insulin responses in young people is limited by lack of normative data. Larger studies are needed to generate Australian screening recommendations. Further assessment of the potential adverse effects of atypical antipsychotic medication on glucose homeostasis in this at-risk group is important.

Aberrant cervical thymus mimicking a cervical mass.

A case of a 9-year-old female with suprasternal extension of the thymus mimicking thyroid gland enlargement is described. Ultrasonography successfully established the diagnosis. Aberrant cervical thymic tissue is an infrequently reported cause of paediatric neck masses. It is important to be aware of this entity to prevent anxiety and inappropriate investigation and/or intervention.

Early adolescent smoking and a web of personal and social disadvantage.

OBJECTIVE: To examine concurrent physical, educational, behavioural, social and family factors associated with cigarette smoking in adolescents at 14 years. METHODOLOGY: This study reports cross-sectional data on 14-year-old adolescents and their mothers, drawn from a prospective cohort study commencing at the time of the first antenatal visit. At 14 years, 5247 adolescents completed questionnaires on current cigarette smoking. Adolescents and mothers completed health, psychological, school and social questionnaires relating to the youth. A total of 3864 adolescents were assessed physically, and undertook the Wide Range Achievement Test (WRAT) and Ravens Progressive Matrices Test. RESULTS: Cigarette smoking at 14 years was associated with externalizing and internalizing behaviour problems, school suspension, contact with children's services and alcohol/illicit drug use. Apart from internalizing behaviour problems, these problems were more prevalent in boys. Poor school performance on maternal/adolescent reports was associated with increased smoking quantity for both genders, though WRAT scores were only decreased in male smokers. The Ravens Progressive Matrices Test scores were lower for boys with greater smoking quantity. The trend was less marked in girls. Body mass index and exercise frequency were not associated with cigarette smoking at 14 years, though girls who smoked had a higher reported prevalence of asthma. Parental smoking, marital conflict, maternal depression, lower income, and mothers aged in their teens and with a lower level of education at the time of this pregnancy were also positively associated with adolescent tobacco use. CONCLUSION: Findings of this study indicate that cigarette smoking, at this critical time of smoking initiation, is associated with a broad spectrum of personal and social disadvantage that needs to be considered in intervention strategies.

Reversible cardiomyopathy in paediatric Addison's disease--a cautionary tale.

A 13 year-old girl with clinical features of Addison's disease developed acute cardiac failure after initiation of treatment and after initial clinical improvement. Large doses of i.v. hydrocortisone and oral fludrocortisone, in addition to inotropic and ventilatory support, were required to achieve cardiovascular stability. The cardiomyopathy improved over one week and her condition then remained stable on oral glucocorticoid and mineralocorticoid replacement therapy. Reversible cardiomyopathy is a rare and potentially life-threatening complication of Addison's disease. The second reported paediatric patient is presented, the only one reported to require ventilatory support.