DNA Polymerase Epsilon Deficiency Causes IMAGe Syndrome with Variable Immunodeficiency.

During genome replication, polymerase epsilon (Pol ε) acts as the major leading-strand DNA polymerase. Here we report the identification of biallelic mutations in POLE, encoding the Pol ε catalytic subunit POLE1, in 15 individuals from 12 families. Phenotypically, these individuals had clinical features closely resembling IMAGe syndrome (intrauterine growth restriction [IUGR], metaphyseal dysplasia, adrenal hypoplasia congenita, and genitourinary anomalies in males), a disorder previously associated with gain-of-function mutations in CDKN1C. POLE1-deficient individuals also exhibited distinctive facial features and variable immune dysfunction with evidence of lymphocyte deficiency. All subjects shared the same intronic variant (c.1686+32C>G) as part of a common haplotype, in combination with different loss-of-function variants in trans. The intronic variant alters splicing, and together the biallelic mutations lead to cellular deficiency of Pol ε and delayed S-phase progression. In summary, we establish POLE as a second gene in which mutations cause IMAGe syndrome. These findings add to a growing list of disorders due to mutations in DNA replication genes that manifest growth restriction alongside adrenal dysfunction and/or immunodeficiency, consolidating these as replisome phenotypes and highlighting a need for future studies to understand the tissue-specific development roles of the encoded proteins.

The "cough trick:" a brief strategy to manage pediatric pain from immunization injections.

OBJECTIVE: The goal was to investigate the effect of a "cough trick" technique on self-reported pain of children receiving routine immunizations. The strategy requires minimal equipment, time, or training for parents, children, and nursing staff members. METHODS: A randomized, controlled, unblinded, within-subject study of 68 children receiving prekindergarten (ages 4-5) or pre-junior high school (ages 11-13) immunizations was performed. Participants were recruited from an outpatient pediatric clinic at a large public hospital in the Midwest. The strategy required a single "warm-up" cough of moderate force, followed by a second cough that coincided with needle puncture. The principle outcome was self-reported pain, although parent and nurse report of pain was used to support the accuracy of self-report. Older participants and all nurses completed a measure of their satisfaction with the procedure. RESULTS: In the initial analysis, the procedure was found not to be effective. However, post hoc tests revealed that the procedure was effective at a statistically and clinically significant level for participants identified as Hispanic white or non-Hispanic white but not for those identified as non-Hispanic black. Participants and clinic nurses found the procedure acceptable and effective. CONCLUSIONS: The results of this study suggest that the cough trick can be an effective strategy for the reduction of pain for some children undergoing routine immunizations. However, additional research is needed to clarify the observed moderation by self-identified race.