11 research outputs found

    Refinement of the critical genomic region for congenital hyperinsulinism in the Chromosome 9p deletion syndrome

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    Version 2; peer review: 3 approved. Available from F1000 Research via the DOI in this recordBackground: Large contiguous gene deletions at the distal end of the short arm of chromosome 9 result in the complex multi-organ condition chromosome 9p deletion syndrome. A range of clinical features can result from these deletions with the most common being facial dysmorphisms and neurological impairment. Congenital hyperinsulinism is a rarely reported feature of the syndrome with the genetic mechanism for the dysregulated insulin secretion being unknown. Methods: We studied the clinical and genetic characteristics of 12 individuals with chromosome 9p deletions who had a history of neonatal hypoglycaemia. Using off-target reads generated from targeted next-generation sequencing of the genes known to cause hyperinsulinaemic hypoglycaemia (n=9), or microarray analysis (n=3), we mapped the minimal shared deleted region on chromosome 9 in this cohort. Targeted sequencing was performed in three patients to search for a recessive mutation unmasked by the deletion. Results: In 10/12 patients with hypoglycaemia, hyperinsulinism was confirmed biochemically. A range of extra-pancreatic features were also reported in these patients consistent with the diagnosis of the Chromosome 9p deletion syndrome. The minimal deleted region was mapped to 7.2 Mb, encompassing 38 protein-coding genes. In silico analysis of these genes highlighted SMARCA2 and RFX3 as potential candidates for the hypoglycaemia. Targeted sequencing performed on three of the patients did not identify a second disease-causing variant within the minimal deleted region. Conclusions: This study identifies 9p deletions as an important cause of hyperinsulinaemic hypoglycaemia and increases the number of cases reported with 9p deletions and hypoglycaemia to 15 making this a more common feature of the syndrome than previously appreciated. Whilst the precise genetic mechanism of the dysregulated insulin secretion could not be determined in these patients, mapping the deletion breakpoints highlighted potential candidate genes for hypoglycaemia within the deleted region.Wellcome TrustRoyal Societ

    Personalized bone reconstruction and regeneration in the treatment of craniosynostosis

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    Craniosynostosis (CS) is the second most prevalent craniofacial congenital malformation due to the premature fusion of skull sutures. CS care requires surgical treatment of variable complexity, aimed at resolving functional and cosmetic defects resulting from the skull growth constrain. Despite significant innovation in the management of CS, morbidity and mortality still exist. Residual cranial defects represent a potential complication and needdedicated management to drive a targeted bone regeneration while modulating suture ossification. To this aim, existing techniques are rapidly evolving and include the implementation of novel biomaterials, 3D printing and additive manufacturing techniques, and advanced therapies based on tissue engineering. This review aims at providing an exhaustive and up\u2010to\u2010date overview of the strategies in use to correct these congenital defects, focusing on the technological advances in the fields of biomaterials and tissue engineering implemented in pediatric surgical skull reconstruction, i.e., biodegradable bone fixation systems, biomimetic scaffolds, drug delivery systems, and cell\u2010based approaches

    A Meta-Analysis of Thyroid-Related Traits Reveals Novel Loci and Gender-Specific Differences in the Regulation of Thyroid Function

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    Studies on serum cholesterol and other coronary heart disease precursors in childhood

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    The change in the pattern of diseases affecting children in industrialised countries during the last century has caused a shift in emphasis from curative to preventive paediatrics. Coronary heart disease (CHD) is one of the major causes of morbidity and mortality in adulthood. Its origins have been shown by epidemiological studies to lie in facets of the Western life style which are biologically disadvantageous. By the time CHD becomes symptomatic, primary prevention is too late; but what is the evidence that by starting these measures in early life benefit would result? The studies described in this thesis were planned to determine whether early deviations from the biological norm occur during childhood for factors known to be associated with CHD in adult life. These factors include blood pressure, personality type, and serum cholesterol. The concentration of cholesterol in serum was chosen because its abnormalities are unequivocally associated with an excess risk of CHD, and because it provides a model for analysis of both genetic and environmental nutritional influences. Although there has been an enormous amount of research into the various influences on serum cholesterol, there is very little data about the subject during the first two years of life when future metabolic homeostatic and nutritional patterns may become established. For that reason a longitudinal study was planned, and the data derived from it was supplemented by cross-sectional studies on older children