Browsing by Author "Russo, Pierre"

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    Clinicopathologic Characterization of Lymphocytic Colitis in the Pediatric Population
    (Sage, 2024) González, Iván A.; Conrad, Maire; Weinbrom, Sarah; Patel, Trusha; Kelsen, Judith R.; Russo, Pierre; Pathology and Laboratory Medicine, School of Medicine
    Background: Lymphocytic colitis (LC) in the pediatric population has been associated with immune dysregulation. Methods: Single-center retrospective study of pediatric LC. Results: 50 patients (35 female, 70%) with a median age of 12 years at diagnosis (interquartile range: 5.7-15.8) of LC were identified. At presentation, 11 patients (22%) had malnutrition, 16 (32%) had a known underlying immune dysregulation, 4 (8%) had celiac disease (CD), and none had a diagnosis of inflammatory bowel disease. The most common medications prior to diagnosis were non-steroidal anti-inflammatory drugs, proton pump inhibitor, and selective serotonin reuptake inhibitors (10% each). Colonic biopsies showed a median number of intraepithelial lymphocytes (IELs)/100 epithelial cells of 48 (range: 25-85), and only 10% of cases had neutrophilic cryptitis. Upper gastrointestinal tract findings included lymphocytic esophagitis (4%), and duodenal IELs without and with villous blunting (9% each) (n: 47). Ten patients (23%) had increased IELs in the terminal ileum (n: 43). Treatments including 5-ASA, budesonide, prednisone, and gluten-free diet improved symptoms in <50% of patients (n: 42), and all follow-up colonoscopies showed persistent LC (n: 13). Conclusion: Our study supports the association of LC with immune-mediated conditions, most commonly celiac disease. Symptomatic improvement was seen in <50% of patients with none of the patients with repeat colonoscopy showing histologic improvement.
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    Identification of PKD1L1 Gene Variants in Children with the Biliary Atresia Splenic Malformation Syndrome
    (Wiley, 2019) Berauer, John-Paul; Mezina, Anya I.; Okou, David T.; Sabo, Aniko; Muzny, Donna M.; Gibbs, Richard A.; Hegde, Madhuri R.; Chopra, Pankaj; Cutler, David J.; Perlmutter, David H.; Bull, Laura N.; Thompson, Richard J.; Loomes, Kathleen M.; Spinner, Nancy B.; Rajagopalan, Ramakrishnan; Guthery, Stephen L.; Moore, Barry; Yandell, Mark; Harpavat, Sanjiv; Magee, John C.; Kamath, Binita M.; Molleston, Jean P.; Bezerra, Jorge A.; Murray, Karen F.; Alonso, Estella M.; Rosenthal, Philip; Squires, Robert H.; Wang, Kasper S.; Finegold, Milton J.; Russo, Pierre; Sherker, Averell H.; Sokol, Ronald J.; Karpen, Saul J.; Pediatrics, School of Medicine
    Biliary atresia (BA) is the most common cause of end‐stage liver disease in children and the primary indication for pediatric liver transplantation, yet underlying etiologies remain unknown. Approximately 10% of infants affected by BA exhibit various laterality defects (heterotaxy) including splenic abnormalities and complex cardiac malformations — a distinctive subgroup commonly referred to as the biliary atresia splenic malformation (BASM) syndrome. We hypothesized that genetic factors linking laterality features with the etiopathogenesis of BA in BASM patients could be identified through whole exome sequencing (WES) of an affected cohort. DNA specimens from 67 BASM subjects, including 58 patient‐parent trios, from the NIDDK‐supported Childhood Liver Disease Research Network (ChiLDReN) underwent WES. Candidate gene variants derived from a pre‐specified set of 2,016 genes associated with ciliary dysgenesis and/or dysfunction or cholestasis were prioritized according to pathogenicity, population frequency, and mode of inheritance. Five BASM subjects harbored rare and potentially deleterious bi‐allelic variants in polycystin 1‐like 1, PKD1L1, a gene associated with ciliary calcium signaling and embryonic laterality determination in fish, mice and humans. Heterozygous PKD1L1 variants were found in 3 additional subjects. Immunohistochemical analysis of liver from the one BASM subject available revealed decreased PKD1L1 expression in bile duct epithelium when compared to normal livers and livers affected by other non‐cholestatic diseases. Conclusion WES identified bi‐allelic and heterozygous PKD1L1 variants of interest in 8 BASM subjects from the ChiLDReN dataset. The dual roles for PKD1L1 in laterality determination and ciliary function suggest that PKD1L1 is a new, biologically plausible, cholangiocyte‐expressed candidate gene for the BASM syndrome.
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    Identification of Polycystic Kidney Disease 1 Like 1 Gene Variants in Children With Biliary Atresia Splenic Malformation Syndrome
    (Wiley, 2019-01-21) Berauer, John-Paul; Mezina, Anya I.; Okou, David T.; Sabo, Aniko; Muzny, Donna M.; Gibbs, Richard A.; Hegde, Madhuri R.; Chopra, Pankaj; Cutler, David J.; Perlmutter, David H.; Bull, Laura N.; Thompson, Richard J.; Loomes, Kathleen M.; Spinner, Nancy B.; Rajagopalan, Ramakrishnan; Guthery, Stephen L.; Moore, Barry; Yandell, Mark; Harpavat, Sanjiv; Magee, John C.; Kamath, Binita M.; Molleston, Jean P.; Bezerra, Jorge A.; Murray, Karen F.; Alonso, Estella M.; Rosenthal, Philip; Squires, Robert H.; Wang, Kasper S.; Finegold, Milton J.; Russo, Pierre; Sherker, Averell H.; Sokol, Ronald J.; Karpen, Saul J.; Pediatrics, School of Medicine
    Biliary atresia (BA) is the most common cause of end-stage liver disease in children and the primary indication for pediatric liver transplantation, yet underlying etiologies remain unknown. Approximately 10% of infants affected by BA exhibit various laterality defects (heterotaxy) including splenic abnormalities and complex cardiac malformations — a distinctive subgroup commonly referred to as the biliary atresia splenic malformation (BASM) syndrome. We hypothesized that genetic factors linking laterality features with the etiopathogenesis of BA in BASM patients could be identified through whole exome sequencing (WES) of an affected cohort. DNA specimens from 67 BASM subjects, including 58 patient-parent trios, from the NIDDK-supported Childhood Liver Disease Research Network (ChiLDReN) underwent WES. Candidate gene variants derived from a pre-specified set of 2,016 genes associated with ciliary dysgenesis and/or dysfunction or cholestasis were prioritized according to pathogenicity, population frequency, and mode of inheritance. Five BASM subjects harbored rare and potentially deleterious bi-allelic variants in polycystin 1-like 1, PKD1L1, a gene associated with ciliary calcium signaling and embryonic laterality determination in fish, mice and humans. Heterozygous PKD1L1 variants were found in 3 additional subjects. Immunohistochemical analysis of liver from the one BASM subject available revealed decreased PKD1L1 expression in bile duct epithelium when compared to normal livers and livers affected by other non-cholestatic diseases. Conclusion: WES identified bi-allelic and heterozygous PKD1L1 variants of interest in 8 BASM subjects from the ChiLDReN dataset. The dual roles for PKD1L1 in laterality determination and ciliary function suggest that PKD1L1 is a new, biologically plausible, cholangiocyte-expressed candidate gene for the BASM syndrome.