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Background and Aims Single-gene mutations cause syndromes of intrahepatic cholestasis, but previous multi-gene mutation screening in children with idiopathic cholestasis failed to fulfill diagnostic criteria in about two-thirds of children. In adults with fibrosing cholestatic disease, heterozygous ABCB4 mutations were present in 34% of patients. Here, we hypothesized that children with idiopathic cholestasis have a higher frequency of heterozygous non-synonymous gene sequence variants. Methods We analyzed the frequency and types of variants in 717 children in whom high-throughput sequencing of the genes SERPINA1, JAG1, ATP8B1, ABCB11, and ABCB4 was performed as part of an evaluation for intrahepatic idiopathic cholestasis. The frequency of non-synonymous variants (NSVs) was compared to those of 1092 control subjects enrolled in the 1000-Genome-Project. Results The frequency of NSVs in single genes was similar between disease (25%) and controls (26%, P=0.518). In contrast, double or triple NSVs in 2 or more genes were more frequent in disease (N= 7%) than controls (N=4.7%, P=0.028). Detailed review of clinical and laboratory information in a subgroup of double or triple heterozygous patients revealed variable GGT levels and severity of pruritus, with liver biopsies showing stage 2–3 fibrosis. Conclusion Children with intrahepatic idiopathic cholestasis have a higher frequency of double or triple NSVs in SERPINA1, JAG1, ATPB1, ABCB11, or ABCB4. These findings raise the potential role for gene-gene relationships in determining the phenotype of cholestatic liver disease in children.

Pediatric patients undergoing small bowel transplantation are susceptible to postoperative CLABSI. SDD directed against enteric microbes is a strategy for reducing CLABSI. We hypothesized that SDD reduces the frequency of CLABSI, infections outside the bloodstream, and allograft rejection during the first 30 days following transplant. A retrospective chart review of 38 pediatric small bowel transplant recipients at CCHMC from 2003 to 2011 was conducted. SDD antimicrobials were oral colistin, tobramycin, and amphotericin B. The incidence of CLABSI, infections outside the bloodstream, and rejection episodes were compared between study periods. The incidence of CLABSI did not difier between study periods (6.9 CLABSI vs. 4.6 CLABSI per 1000 catheter days; p = 0.727), but gram positives and Candida predominated in the first 30 days. Incidence of bacterial infections outside the bloodstream did not differ (p = 0.227). Rejection occurred more frequently during the first month following transplant (p = 0.302). SDD does not alter the incidence of CLABSI, bacterial infections outside the bloodstream, or allograft rejection in the immediate 30 days post-transplantation. However, SDD does influence CLABSI organism types (favoring gram positives and Candida) and Candidal infections outside the bloodstream.

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