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Barron M.A.,Canadian Center for Primary Immunodeficiency | Makhija M.,Canadian Center for Primary Immunodeficiency | Hagen L.E.M.,Canadian Center for Primary Immunodeficiency | Pencharz P.,Hospital for Sick Children | And 6 more authors.
Journal of Pediatrics | Year: 2011

Objectives: To measure resting energy expenditure (REE) and determine whether increased REE (hypermetabolism) is associated with failure to thrive (FTT) in patients with severe combined immunodeficiency (SCID) at diagnosis. Study design: REE was measured in 26 patients with SCID in a single transplant center. Predicted REE was determined with World Health Organization standards. Measured REE >110% of predicted REE was classified as hypermetabolism. Other data collected included FTT status, infections, genotype, phenotype, and the feeding methods used. Results: Fifteen of 26 patients (57.7%) had FTT, and 18 of 26 patients (69.2%) were hypermetabolic. Hypermetabolism occured in 14 of 15 patients (93%) with FTT, and only 4 of 11 patients (36%) without FTT had hypermetabolism (P =.003). There was a significant difference between the measured REE (71.75 ± 16.6 kcal/kg) and the predicted REE (52.85 ± 2.8 kcal/kg; P <.0001). Eleven of 17 patients (65%) required nasogastric feeding, parenteral nutrition, or both to meet their energy needs. Conclusions: Hypermetabolism is common in patients with SCID and may contribute to the development of FTT. The hypermetabolism in these patients may necessitate intensive nutrition support. © 2011 Mosby Inc. All rights reserved.

Merico D.,Applied Genomics | Roifman M.,Hospital for Sick Children | Roifman M.,University of Toronto | Braunschweig U.,University of Toronto | And 23 more authors.
Nature Communications | Year: 2015

Roifman Syndrome is a rare congenital disorder characterized by growth retardation, cognitive delay, spondyloepiphyseal dysplasia and antibody deficiency. Here we utilize whole-genome sequencing of Roifman Syndrome patients to reveal compound heterozygous rare variants that disrupt highly conserved positions of the RNU4ATAC small nuclear RNA gene, a minor spliceosome component that is essential for minor intron splicing. Targeted sequencing confirms allele segregation in six cases from four unrelated families. RNU4ATAC rare variants have been recently reported to cause microcephalic osteodysplastic primordial dwarfism, type I (MOPD1), whose phenotype is distinct from Roifman Syndrome. Strikingly, all six of the Roifman Syndrome cases have one variant that overlaps MOPD1-implicated structural elements, while the other variant overlaps a highly conserved structural element not previously implicated in disease. RNA-seq analysis confirms extensive and specific defects of minor intron splicing. Available allele frequency data suggest that recessive genetic disorders caused by RNU4ATAC rare variants may be more prevalent than previously reported. © 2015 Macmillan Publishers Limited. All rights reserved.

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