Evaluation of Severe Combined Immunodeficiency and Combined Immunodeficiency Pediatric Patients on the Basis of Cellular Radiosensitivity.

Abstract

Pediatric patients with severe or nonsevere combined immunodeficiency have increased susceptibility to severe, life-threatening infections and, without hematopoietic stem cell transplantation, may fail to thrive. A subset of these patients have the radiosensitive (RS) phenotype, which may necessitate conditioning before hematopoietic stem cell transplantation, and this conditioning includes radiomimetic drugs, which may significantly affect treatment response. To provide statistical criteria for classifying cellular response to ionizing radiation as the measure of functional RS screening, we analyzed the repair capacity and survival of ex vivo irradiated primary skin fibroblasts from five dysmorphic and/or developmentally delayed pediatric patients with severe combined immunodeficiency and combined immunodeficiency. We developed a mathematical framework for the analysis of γ histone 2A isoform X foci kinetics to quantitate DNA-repair capacity, thus establishing crucial criteria for identifying RS. The results, presented in a diagram showing each patient as a point in a 2D RS map, were in agreement with findings from the assessment of cellular RS by clonogenic survival and from the genetic analysis of factors involved in the nonhomologous end-joining repair pathway. We provide recommendations for incorporating into clinical practice the functional assays and genetic analysis used for establishing RS status before conditioning. This knowledge would enable the selection of the most appropriate treatment regimen, reducing the risk for severe therapy-related adverse effects.

• Authors: Pavel Lobachevsky, Lisa Woodbine, Kuang-Chih Hsiao, Sharon Choo, Chris Fraser, Paul Gray, Jai Smith, Nickala Best, Laura Munforte, Elena Korneeva, Roger F Martin, Penny A Jeggo, Olga A Martin
• Journal: The Journal of molecular diagnostics : JMD (J Mol Diagn) Vol. 17 Issue 5 Pg. 560-75 (Sep 2015) ISSN: 1943-7811 [Electronic] United States
• PMID: 26151233 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.

Topics

• Adolescent
• Cells, Cultured
• Child
• Child, Preschool
• Female
• Fibroblasts (pathology, radiation effects)
• Humans
• Infant
• Male
• Phenotype
• Radiation Tolerance (physiology)
• Severe Combined Immunodeficiency (diagnosis, pathology)
• Skin (pathology, radiation effects)