Publications by authors named "David A Piccoli"

65 Publications

Evaluating the biocontrol potential of Canadian strain Bacillus velezensis 1B-23 via its surfactin production at various pHs and temperatures.

BMC Biotechnol 2021 Apr 29;21(1):31. Epub 2021 Apr 29.

Department of Microbiology and Immunology, University of Western Ontario, 1151 Richmond Street, London, Ontario, N6A 5B7, Canada.

Background: Microorganisms, including Bacillus species are used to help control plant pathogens, thereby reducing reliance on synthetic pesticides in agriculture. Bacillus velezensis strain 1B-23 has been shown to reduce symptoms of bacterial disease caused by Clavibacter michiganensis subsp. michiganensis in greenhouse-grown tomatoes, with in vitro studies implicating the lipopeptide surfactin as a key antimicrobial. While surfactin is known to be effective against many bacterial pathogens, it is inhibitory to a smaller proportion of fungi which nonetheless cause the majority of crop diseases. In addition, knowledge of optimal conditions for surfactin production in B. velezensis is lacking.

Results: Here, B. velezensis 1B-23 was shown to inhibit in vitro growth of 10 fungal strains including Candida albicans, Cochliobolus carbonum, Cryptococcus neoformans, Cylindrocarpon destructans Fusarium oxysporum, Fusarium solani, Monilinia fructicola, and Rhizoctonia solani, as well as two strains of C. michiganensis michiganensis. Three of the fungal strains (C. carbonum, C. neoformans, and M. fructicola) and the bacterial strains were also inhibited by purified surfactin (surfactin C, or [Leu7] surfactin C15) from B. velezensis 1B-23. Optimal surfactin production occurred in vitro at a relatively low temperature (16 °C) and a slightly acidic pH of 6.0. In addition to surfactin, B. velenzensis also produced macrolactins, cyclic dipeptides and minor amounts of iturins which could be responsible for the bioactivity against fungal strains which were not inhibited by purified surfactin C.

Conclusions: Our study indicates that B. velezensis 1B-23 has potential as a biocontrol agent against both bacterial and fungal pathogens, and may be particularly useful in slightly acidic soils of cooler climates.
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http://dx.doi.org/10.1186/s12896-021-00690-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8082884PMC
April 2021

Alagille syndrome and risk for hepatocellular carcinoma: Need for increased surveillance in adults with mild liver phenotypes.

Am J Med Genet A 2021 03 24;185(3):719-731. Epub 2020 Dec 24.

Division of Pediatric Gastroenterology, Hepatology and Nutrition, Children's Hospital of Philadelphia and Department of Pediatrics, The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Alagille syndrome (ALGS) is a multisystem autosomal dominant developmental disorder caused predominantly by pathogenic variants in JAGGED1 (JAG1), and also by pathogenic variants in NOTCH2 in a much smaller number of individuals. Clinical presentation is highly variable and includes liver, heart, eye, skeleton, and facial abnormalities, with a subset of individuals also presenting with kidney, vascular, and central nervous system phenotypes. Hepatocellular carcinoma (HCC) is a rare complication of ALGS, though little is known about its incidence or etiology among affected individuals. Previous reports have identified HCC occurrence in both pediatric and adult cases of ALGS. We present a case report of HCC in a 58-year-old woman with a pathogenic JAG1 variant and no overt hepatic features of ALGS. Through a comprehensive literature review, we compile all reported pediatric and adult cases, and further highlight one previously reported case of HCC onset in an adult ALGS patient without any hepatic disease features, similar to our own described patient. Our case report and literature review suggest that ALGS-causing variants could confer risk for developing HCC regardless of phenotypic severity and highlight a need for a cancer screening protocol that would enable early detection and treatment in this at-risk population.
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http://dx.doi.org/10.1002/ajmg.a.62028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898517PMC
March 2021

Outcomes of Childhood Cholestasis in Alagille Syndrome: Results of a Multicenter Observational Study.

Hepatol Commun 2020 Mar 22;4(3):387-398. Epub 2020 Jan 22.

University of Colorado School of Medicine Children's Hospital Colorado Aurora CO.

Alagille syndrome (ALGS) is an autosomal dominant multisystem disorder with cholestasis as a defining clinical feature. We sought to characterize hepatic outcomes in a molecularly defined cohort of children with ALGS-related cholestasis. Two hundred and ninety-three participants with ALGS with native liver were enrolled. Participants entered the study at different ages and data were collected retrospectively prior to enrollment, and prospectively during the study course. Genetic analysis in 206 revealed mutations in 91% and mutations in 4%. Growth was impaired with mean height and weight -scores of <-1.0 at all ages. Regression analysis revealed that every 10 mg/dL increase in total bilirubin was associated with a decrease in height -score by 0.10 ( = 0.03) and weight -score by 0.15 ( = 0.007). Total bilirubin was higher for younger participants ( = 0.03) with a median of 6.9 mg/dL for those less than 1 year old compared with a median of 1.3 mg/dL for participants 13 years or older. The median gamma glutamyl transferase also dropped from 612 to 268 in the same age groups. After adjusting for age, there was substantial within-individual variation of alanine aminotransferase. By 20 years of age, 40% of participants had developed definite portal hypertension. Estimated liver transplant-free survival at the age of 18.5 years was 24%. : This is the largest multicenter natural history study of cholestasis in ALGS, demonstrating a previously underappreciated burden of liver disease with early profound cholestasis, a second wave of portal hypertension later in childhood, and less than 25% of patients reaching young adulthood with their native liver. These findings will promote optimization of ALGS management and development of clinically relevant endpoints for future therapeutic trials.
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http://dx.doi.org/10.1002/hep4.1468DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7049675PMC
March 2020

Genome sequencing increases diagnostic yield in clinically diagnosed Alagille syndrome patients with previously negative test results.

Genet Med 2021 Feb 20;23(2):323-330. Epub 2020 Oct 20.

Division of Genomic Diagnostics, Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.

Purpose: Detection of all major classes of genomic variants in a single test would decrease cost and increase the efficiency of genomic diagnostics. Genome sequencing (GS) has the potential to provide this level of comprehensive detection. We sought to demonstrate the utility of GS in the molecular diagnosis of 18 patients with clinically defined Alagille syndrome (ALGS), who had a negative or inconclusive result by standard-of-care testing.

Methods: We performed GS on 16 pathogenic variant-negative probands and two probands with inconclusive results (of 406 ALGS probands) and analyzed the data for sequence, copy-number, and structural variants in JAG1 and NOTCH2.

Results: GS identified four novel pathogenic alterations including a copy-neutral inversion, a partial deletion, and a promoter variant in JAG1, and a partial NOTCH2 deletion, for an additional diagnostic yield of 0.9%. Furthermore, GS resolved two complex rearrangements, resulting in identification of a pathogenic variant in 97.5% (n = 396/406) of patients after GS.

Conclusion: GS provided an increased diagnostic yield for individuals with clinically defined ALGS who had prior negative or incomplete genetic testing by other methods. Our results show that GS can detect all major classes of variants and has potential to become a single first-tier diagnostic test for Mendelian disorders.
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http://dx.doi.org/10.1038/s41436-020-00989-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862053PMC
February 2021

Bone geometry and microarchitecture deficits in children with Alagille syndrome.

Bone 2020 12 11;141:115576. Epub 2020 Aug 11.

Division of Gastroenterology, Hepatology and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, PA, United States of America; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States of America. Electronic address:

Alagille syndrome (ALGS) is an autosomal dominant disorder attributed to mutations in the Notch signaling pathway. Children with ALGS are at increased risk for fragility fracture of unknown etiology. Our objective was to characterize bone mass, geometry, and microarchitecture in children with ALGS. This was a cross-sectional study of 10 children (9 females), ages 8-18 years, with a clinical diagnosis of ALGS. Bone density was assessed via DXA (Hologic Discovery A) at several skeletal regions. Tibia trabecular and cortical bone was assessed via pQCT (Stratec XCT 2000) at the distal 3% and 38% sites, respectively. Tibia bone microarchitecture was assessed via HR-pQCT (Scanco XtremeCT II) at an ultradistal site located at 4% of tibia length and a cortical site at 30% of tibia length. Z-scores were calculated for DXA and pQCT measures. In the absence of XtremeCT II HR-pQCT reference data, these outcome measures were descriptively compared to a sample of healthy children ages 5-20 years (n = 247). Anthropometrics and labs were also collected. Based on one-sample t-tests, mean Z-scores for height and weight (both p < .05), were significantly less than zero. DXA bone Z-scores were not significantly different from zero, but were highly variable. For pQCT bone measures, Z-scores for total bone mineral content at the distal 3% site and cortical bone mineral content, cortical area, and cortical thickness at the distal 38% site were significantly less than zero (all p < .05). There was good correspondence between pQCT measures of cortical thickness Z-scores and DXA Z-scores for aBMD at the whole body less head, 1/3 radius, and femoral neck (all p < .05). Compared to healthy children, those with ALGS generally had lower trabecular number and greater trabecular separation despite having greater trabecular thickness (measured via HR-pQCT). Bilirubin and bile acids, markers of hepatic cholestasis, were associated with poorer bone measures. For example, greater bilirubin was associated with lower trabecular number (Spearman's rho [ρ] = -0.82, p = .023) and greater trabecular separation (ρ = 0.82, p = .023) measured via HR-pQCT, and greater bile acids were associated with lower cortical area measured via pQCT (ρ = -0.78, p = .041) and lower serum insulin-like growth factor-1 (ρ = -0.86, p = .002). In summary, deficits in cortical bone size and trabecular bone microarchitecture were evident in children with ALGS. Further investigation is needed to understand the factors contributing to these skeletal inadequacies, and the manner in which these deficits contribute to increased fracture risk.
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http://dx.doi.org/10.1016/j.bone.2020.115576DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7680312PMC
December 2020

Protein-elongating mutations in MYH11 are implicated in a dominantly inherited smooth muscle dysmotility syndrome with severe esophageal, gastric, and intestinal disease.

Hum Mutat 2020 05 6;41(5):973-982. Epub 2020 Feb 6.

Division of Genomic Diagnostics, Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia and The Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.

Gastrointestinal motility disorders include a spectrum of mild to severe clinical phenotypes that are caused by smooth muscle dysfunction. We investigated the genetic etiology of severe esophageal, gastric, and colonic dysmotility in two unrelated families with autosomal dominant disease presentation. Using exome sequencing, we identified a 2 base pair insertion at the end of the myosin heavy chain 11 (MYH11) gene in all affected members of Family 1 [NM_001040113:c.5819_5820insCA(p.Gln1941Asnfs*91)] and a 1 base pair deletion at the same genetic locus in Proband 2 [NM_001040113:c.5819del(p.Pro1940Hisfs*91)]. Both variants are predicted to result in a similarly elongated protein product. Heterozygous dominant negative MYH11 pathogenic variants have been associated with thoracic aortic aneurysm and dissection while biallelic null alleles have been associated with megacystis microcolon intestinal hypoperistalsis syndrome. This report highlights heterozygous protein-elongating MYH11 variants affecting the SM2 isoforms of MYH11 as a cause for severe gastrointestinal dysmotility, and we hypothesize that the mechanistic pathogenesis of this disease, dominant hypercontractile loss-of-function, is distinct from those implicated in other diseases involving MYH11 dysfunction.
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http://dx.doi.org/10.1002/humu.23986DOI Listing
May 2020

Alagille syndrome mutation update: Comprehensive overview of JAG1 and NOTCH2 mutation frequencies and insight into missense variant classification.

Hum Mutat 2019 12 26;40(12):2197-2220. Epub 2019 Aug 26.

Division of Genomic Diagnostics, Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia and The Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.

Alagille syndrome is an autosomal dominant disease with a known molecular etiology of dysfunctional Notch signaling caused primarily by pathogenic variants in JAGGED1 (JAG1), but also by variants in NOTCH2. The majority of JAG1 variants result in loss of function, however disease has also been attributed to lesser understood missense variants. Conversely, the majority of NOTCH2 variants are missense, though fewer of these variants have been described. In addition, there is a small group of patients with a clear clinical phenotype in the absence of a pathogenic variant. Here, we catalog our single-center study, which includes 401 probands and 111 affected family members amassed over a 27-year period, to provide updated mutation frequencies in JAG1 and NOTCH2 as well as functional validation of nine missense variants. Combining our cohort of 86 novel JAG1 and three novel NOTCH2 variants with previously published data (totaling 713 variants), we present the most comprehensive pathogenic variant overview for Alagille syndrome. Using this data set, we developed new guidance to help with the classification of JAG1 missense variants. Finally, we report clinically consistent cases for which a molecular etiology has not been identified and discuss the potential for next generation sequencing methodologies in novel variant discovery.
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http://dx.doi.org/10.1002/humu.23879DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6899717PMC
December 2019

Intrahepatic dynamic contrast MR lymphangiography: initial experience with a new technique for the assessment of liver lymphatics.

Eur Radiol 2019 Oct 18;29(10):5190-5196. Epub 2019 Mar 18.

Division of Cardiology, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, 3401 Civic Center Blvd, Philadelphia, PA, 19104, USA.

Objectives: To describe the technique and report on our initial experience with the use of intrahepatic dynamic contrast magnetic resonance lymphangiography (IH-DCMRL) for evaluation of the lymphatics in patients with hepatic lymphatic flow disorders.

Methods: This is a retrospective review of the imaging and clinical findings in six consecutive patients undergoing IH-DCMRL. The technique involves injection of a gadolinium contrast agent into the intrahepatic lymphatic ducts followed by imaging of the abdomen and chest with both heavily T2-weighted imaging and dynamic time-resolved imaging.

Results: In six consecutive patients, IH-DCMRL was technically successful. There were four patients with protein-losing enteropathy (PLE) and two with ascites in this study. In the four patients with PLE, IH-DCMRL demonstrated hepatoduodenal connections with leak of contrast into the duodenal lumen not seen by conventional lymphangiography. In one patient with ascites, IH-DCMRL demonstrated lymphatic leakage into the peritoneal cavity not seen by intranodal lymphangiography. In the second patient with ascites, retrograde lymphatic perfusion of mesenteric lymphatic networks and nodes was seen. Venous contamination was seen in two patients. No biliary contamination was identified. There were no short-term complications.

Conclusions: IH-DCMRL is a cross-sectional technique which successfully evaluated hepatic lymphatic flow disorders and warrants further investigation.

Key Points: • Intrahepatic dynamic contrast magnetic resonance lymphangiography (IH-DCMRL) is a new imaging technique to evaluate hepatic lymphatic flow disorders such as protein-losing enteropathy. • In comparison to conventional liver lymphangiography, IH-DCMRL offers a 3D imaging technique and better distal lymphatic contrast distribution and does not use ionizing radiation.
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http://dx.doi.org/10.1007/s00330-019-06112-zDOI Listing
October 2019

Recommendations for Diagnosis and Management of Autoimmune Pancreatitis in Childhood: Consensus From INSPPIRE.

J Pediatr Gastroenterol Nutr 2018 08;67(2):232-236

Hospital for Sick Children, Toronto, Ontario, Canada.

Objectives: Autoimmune pancreatitis (AIP) represents a complex immune-mediated pancreas disorder. Pediatric AIP (P-AIP) is rare. We have recently summarized the characteristic features of P-AIP. We now aim to develop recommendation statements to standardize the diagnostic and therapeutic approach to P-AIP and facilitate future research in the field.

Methods: A panel of pediatric gastroenterologists participating in the International Study Group of Pediatric Pancreatitis: In search for a cuRE was formed to discuss and then vote on 15 recommendation statements. A consensus of at least 80% was obtained following 3 voting rounds and revision of the statements.

Results: We have now generated 15 statements to help standardize the approach to diagnosis and management of P-AIP.

Conclusions: The first P-AIP recommendation statements developed by the International Study Group of Pediatric Pancreatitis: In search for a cuRE group are intended to bring standardization to the diagnosis and treatment of this rare childhood disorder. These statements may help guide a uniform approach to patient care and facilitate future research studies.
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http://dx.doi.org/10.1097/MPG.0000000000002028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6059991PMC
August 2018

Histological features of ileitis differentiating pediatric Crohn disease from ulcerative colitis with backwash ileitis.

Dig Liver Dis 2018 Feb 19;50(2):147-153. Epub 2017 Oct 19.

The Children's Hospital of Philadelphia, Division of Pediatric Gastroenterology, Hepatology, & Nutrition, Philadelphia, PA, United States.

Background/aim: Pediatric ileocolonic Crohn disease (CD) may be difficult to distinguish from ulcerative colitis (UC) with backwash ileitis (BWI). The primary aim of the study was to determine the probability of CD in children with a confluent colitis and ileitis when newly diagnosed with inflammatory bowel disease (IBD).

Methods: A retrospective observational study of 100 newly diagnosed patients with IBD was performed. Two pathologists reviewed ileal biopsy specimens for 8 histological features. Biopsy and clinical features were evaluated for predictive ability of a final diagnosis of CD.

Results: The presence of crypt distortion, lamina propria (LP) expansion, and acute LP inflammation combined with 4 clinical variables in multivariate regression analysis had adequate discriminative validity when comparing the mean probability of a final CD diagnosis between CD and not-CD groups (0.90 vs. 0.59, p value <0.001). When crypt distortion, LP expansion, and acute LP inflammation are present in any combination, the sensitivity and specificity for presence of CD ranges 38.4-57% and 92.9-100%, respectively.

Conclusions: Combining histological features of ileitis and clinical variables can adequately discriminate between the presence and absence of Crohn disease in children who present with confluent colitis and ileitis. Combined presence of certain histological features has high specificity for CD.
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http://dx.doi.org/10.1016/j.dld.2017.10.006DOI Listing
February 2018

Protein-Losing Enteropathy in Patients With Congenital Heart Disease.

J Am Coll Cardiol 2017 Jun;69(24):2929-2937

Center for Lymphatic Imaging and Interventions, Children's Hospital of Philadelphia/Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania.

Background: Protein-losing enteropathy (PLE), characterized by loss of proteins in the intestine, is a devastating complication in patients with congenital heart disease. The cause of PLE is unknown, but lymphatic involvement has been suspected.

Objectives: The authors evaluated the use of lymphangiographic imaging and liver lymphatic embolization as a treatment for PLE.

Methods: This was a single-center, retrospective review of imaging and interventions used in 8 consecutive patients with liver lymphatic embolization and congenital heart disease with elevated central venous pressure complicated by PLE.

Results: Liver lymphangiography was performed in 8 patients (5 males, 3 females; median age, 21 years), 7 of whom demonstrated leakage of liver lymph into the duodenum through abnormal hepatoduodenal lymphatic communications. This was confirmed by duodenoscopy with simultaneous injection of isosulfan blue dye into the liver lymphatics in 6 of 7 patients. Liver lymphatic embolization with ethiodized oil in 2 patients resulted in a temporary increase in albumin blood level and symptom improvement in 1 patient, but was complicated by duodenal bleeding in both patients. Of the remaining 6 patients, liver lymphatic embolization with n-butyl cyanoacrylate glue resulted in sustained improvement of the serum albumin level and symptoms in 3 patients, temporary improvement in 2 patients, and no change in 1 patient with median follow-up of 135 days (range, 84 to 1,005 days).

Conclusions: The authors demonstrated liver lymph leakage as a cause of PLE in patients with congenital heart disease and elevated central venous pressure. Lymphatic embolization led to improved albumin levels and relief of symptoms. Further experience with the technique is needed to determine long-term outcome of this procedure.
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http://dx.doi.org/10.1016/j.jacc.2017.04.023DOI Listing
June 2017

Autoimmune Pancreatitis in Children: Characteristic Features, Diagnosis, and Management.

Am J Gastroenterol 2017 Oct 4;112(10):1604-1611. Epub 2017 Apr 4.

Hospital for Sick Children, Toronto, Ontario, Canada.

Objectives: Autoimmune pancreatitis (AIP) is an increasingly recognized disease entity, but data in children are limited. AIP presentation and outcome in children might differ from the adult experience. We aim to determine the characteristic features of AIP in children.

Methods: Data about clinical symptoms, imaging, histology, and treatment were collected using two sources: (i) a systematic literature search and (ii) the INSPPIRE database, the largest international multicenter study of pancreatitis in children and the Cliniques Universitaires St-Luc (CUSL) registry.

Results: We identified 48 AIP cases: 30 from literature review, 14 from INSPPIRE, and 4 from CUSL. The median age at diagnosis was 13 years (range 2-17 years). Abdominal pain (43/47, 91%) and/or obstructive jaundice (20/47, 42%) were the most common symptoms at diagnosis. Elevated serum IgG4 levels were only observed in 9/40 (22%) children. Cross-sectional imaging studies were abnormal in all children including hypointense global or focal gland enlargement (39/47, 83%), main pancreatic duct irregularity (30/47, 64%), and common bile duct stricture (26/47, 55%). A combination of lymphoplasmacytic inflammation, pancreatic fibrosis, and ductal granulocyte infiltration were the main histological findings (18/25, 72%). Children with AIP had a prompt clinical response to steroids. Complications of AIP included failure of exocrine (4/25, 16%) and endocrine (3/27, 11%) pancreas function.

Conclusions: Pediatric AIP has a distinct presentation with features similar to type 2 AIP in adults. This comprehensive report on the largest group of children with AIP to date is expected to help with the diagnosis and management of this disease and pave the way for future research studies.
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http://dx.doi.org/10.1038/ajg.2017.85DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5908471PMC
October 2017

Anterior Chamber Pathology in Alagille Syndrome.

Ocul Oncol Pathol 2016 Oct 2;2(4):270-275. Epub 2016 Jul 2.

Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, Pa., USA; Wills Eye Hospital, Philadelphia, Pa., USA.

Background: Alagille syndrome is an autosomal dominant disorder characterized by neonatal cholestasis, characteristic facies, and cardiac abnormalities. Ocular abnormalities include posterior embryotoxon, mosaic pattern of iris stromal hypoplasia, microcornea, optic disc drusen, and pigmentary retinopathy. We present the second report of ocular pathology in two cases of Alagille syndrome.

Methods: Gross and histologic preparations of four eyes of two patients.

Results: Posterior embryotoxon is seen in both cases, with iris processes extending to the embryotoxon in case 1. Case 1 exhibited distinctly abnormal iris stroma with a prominent cleft separating the anterior and posterior stroma. Lacy vacuolization of the iris pigment epithelium was seen in case 2.

Conclusions: Alagille syndrome is primarily a hepatic disorder but presents with several distinct ocular pathologic features, most specifically posterior embryotoxon. This and the unusual iris stroma may be caused by improper migration of neural crest cells due to mutation in the gene that causes Alagille syndrome. Patients with Alagille syndrome rarely present to ocular autopsy. Pathology findings may help us better understand the pathophysiology of the ocular abnormalities in this disorder.
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http://dx.doi.org/10.1159/000446804DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5091199PMC
October 2016

Vedolizumab Therapy in Severe Pediatric Inflammatory Bowel Disease.

Inflamm Bowel Dis 2016 10;22(10):2425-31

*Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; †Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; and ‡Department of Biomedical Health Informatics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.

Background: Vedolizumab is effective for inducing and maintaining remission in adults with inflammatory bowel disease (IBD); however, there is limited pediatric data. This study aimed to describe the adverse events and clinical response to vedolizumab in refractory pediatric IBD.

Methods: Disease activity indices, clinical response, concomitant medication use, and adverse events were measured over 22 weeks in an observational prospective cohort study of children with refractory IBD who had failed anti-tumor necrosis factor therapy and subsequently initiated vedolizumab therapy.

Results: Twenty-one subjects, 16 with Crohn disease, received vedolizumab. Clinical response was observed in 6/19 (31.6%) of the evaluable subjects at week 6 and in 11/19 (57.9%) by week 22. Before induction, 15/21 (71.4%) participants were treated with systemic corticosteroids, as compared with 7/21 (33.3%) subjects at 22 weeks. Steroid-free remission was seen in 1/20 (5.0%) subjects at 6 weeks, 3/20 (15.0%) at 14 weeks, and 4/20 (20.0%) at 22 weeks. There was statistically significant improvement in serum albumin and hematocrit; however, C-reactive protein increased by week 22 (P < 0.05). There were no infusion reactions. Vedolizumab was discontinued in 2 patients because of severe colitis, requiring surgical intervention.

Conclusions: There is limited experience with vedolizumab therapy in pediatric IBD. There seems to be a marked number of subjects with clinical response in the first 6 weeks that increases further by week 22 despite the severity of disease in this cohort. Adverse events may not be directly related to vedolizumab. This study is limited by small sample size, and larger prospective studies are warranted.
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http://dx.doi.org/10.1097/MIB.0000000000000918DOI Listing
October 2016

Chromosome 10q23 Deletion Syndrome: An Overlap of Bannayan-Riley-Ruvalcaba Syndrome and Juvenile Polyposis Syndrome.

J Paediatr Child Health 2016 Aug;52(8):852

Division of Gastroenterology, Hepatology and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States.

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http://dx.doi.org/10.1111/jpc.13289DOI Listing
August 2016

Severe Eosinophilic Gastroenteritis in a Crohn's Disease Patient Treated With Infliximab and Adalimumab.

Am J Gastroenterol 2016 Mar;111(3):437-8

Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

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http://dx.doi.org/10.1038/ajg.2015.438DOI Listing
March 2016

Compound heterozygous mutations in NEK8 in siblings with end-stage renal disease with hepatic and cardiac anomalies.

Am J Med Genet A 2016 Mar 24;170(3):750-3. Epub 2015 Dec 24.

Division of Genomic Diagnostics, Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, and The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.

We studied two brothers who presented in the newborn period with cardiac, renal, and hepatic anomalies that were initially suggestive of ALGS, although no mutations in JAG1 or NOTCH2 were identified. Exome sequencing demonstrated compound heterozygous mutations in the NEK8 gene (Never in mitosis A-related Kinase 8), a ciliary kinase indispensable for cardiac and renal development based on murine studies. The mutations included a c.2069_2070insC variant (p.Ter693LeufsTer86), and a c.1043C>T variant (p.Thr348Met) in the highly conserved RCC1 (Regulation of Chromosome Condensation 1) domain. The RCC1 domain is crucial for localization of the NEK8 protein to the centrosomes and cilia. Mutations in NEK8 have been previously reported in three fetuses (from a single family) with renal-hepatic-pancreatic dysplasia 2 (RHPD2), similar to Ivemark syndrome, and in three individuals with nephronophthisis (NPHP9). This is the third report of disease-causing mutations in the NEK8 gene in humans and only the second describing multi-organ involvement. The clinical features we describe differ from those in the previously published report in that (1) a pancreatic phenotype was not observed in the individuals reported here, (2) there were more prominent cardiac findings, (consistent with observations in murine models), and (3) we observed bile duct hypoplasia rather than ductal plate malformation. The patients reported here expand our understanding of the NEK8-associated phenotype. Our findings highlight the variable phenotypic expressivity and the spectrum of clinical manifestations due to mutations in the NEK8 gene.
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http://dx.doi.org/10.1002/ajmg.a.37512DOI Listing
March 2016

Erratum to: A de novo whole gene deletion of XIAP detected by exome sequencing analysis in very early onset inflammatory bowel disease: a case report.

BMC Gastroenterol 2015 Dec 18;15:179. Epub 2015 Dec 18.

Division of Human Genetics, The Children's Hospital of Philadelphia, Department of Pediatrics, Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania; Department of Molecular Medicine, University Sapienza, Rome, Italy.

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http://dx.doi.org/10.1186/s12876-015-0412-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4683708PMC
December 2015

A de novo whole gene deletion of XIAP detected by exome sequencing analysis in very early onset inflammatory bowel disease: a case report.

BMC Gastroenterol 2015 Nov 18;15:160. Epub 2015 Nov 18.

Division of Human Genetics, The Children's Hospital of Philadelphia, Department of Pediatrics, Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania; Department of Molecular Medicine, University Sapienza, Rome, Italy.

Background: Children with very early-onset inflammatory bowel disease (VEO-IBD), those diagnosed at less than 5 years of age, are a unique population. A subset of these patients present with a distinct phenotype and more severe disease than older children and adults. Host genetics is thought to play a more prominent role in this young population, and monogenic defects in genes related to primary immunodeficiencies are responsible for the disease in a small subset of patients with VEO-IBD.

Case Presentation: We report a child who presented at 3 weeks of life with very early-onset inflammatory bowel disease (VEO-IBD). He had a complicated disease course and remained unresponsive to medical and surgical therapy. The refractory nature of his disease, together with his young age of presentation, prompted utilization of whole exome sequencing (WES) to detect an underlying monogenic primary immunodeficiency and potentially target therapy to the identified defect. Copy number variation analysis (CNV) was performed using the eXome-Hidden Markov Model. Whole exome sequencing revealed 1,380 nonsense and missense variants in the patient. Plausible candidate variants were not detected following analysis of filtered variants, therefore, we performed CNV analysis of the WES data, which led us to identify a de novo whole gene deletion in XIAP.

Conclusion: This is the first reported whole gene deletion in XIAP, the causal gene responsible for XLP2 (X-linked lymphoproliferative Disease 2). XLP2 is a syndrome resulting in VEO-IBD and can increase susceptibility to hemophagocytic lymphohistocytosis (HLH). This identification allowed the patient to be referred for bone marrow transplantation, potentially curative for his disease and critical to prevent the catastrophic sequela of HLH. This illustrates the unique etiology of VEO-IBD, and the subsequent effects on therapeutic options. This cohort requires careful and thorough evaluation for monogenic defects and primary immunodeficiencies.
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http://dx.doi.org/10.1186/s12876-015-0394-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4652404PMC
November 2015

Early life predictive markers of liver disease outcome in an International, Multicentre Cohort of children with Alagille syndrome.

Liver Int 2016 05 18;36(5):755-60. Epub 2015 Aug 18.

Division of Gastroenterology, Hepatology and Nutrition, Hospital for Sick Children, University of Toronto, Toronto, Canada.

Background & Aims: Liver disease in Alagille syndrome is highly variable. Many of the patients presenting with severe cholestasis early in life improve spontaneously; 10-20%, however, have progressive disease. It is currently not possible to predict long-term hepatic outcomes in Alagille syndrome. This international, multicentre study was aimed at identifying early life predictors of liver disease outcome.

Methods: Retrospective clinical, laboratory and radiographic data from a cohort of 144 Alagille syndrome patients, whose long-term hepatic outcomes had been determined a priori based on previously published criteria, were collected.

Results: Sixty-seven patients had mild and 77 had severe hepatic outcome. Univariate analysis demonstrated that cholestasis and fibrosis on biopsy, as well as the presence of xanthomata were significantly different between the groups (P < 0.05 for all). Mixed model analysis revealed that total serum bilirubin and serum cholesterol were also associated with outcome (P = 0.001 and P = 0.002, respectively). Graphical representation of the data revealed a change in total bilirubin levels between 12 and 24 months of age in the mild group. Recursive partitioning identified a threshold for total bilirubin of 3.8 mg/dl (65 mmol/L) in that age-frame that differentiated between outcomes. A multivariable logistic regression model was developed using fibrosis, xanthomata and the total bilirubin cut-off of 3.8 mg/dl (65 mmol/L), which generated an area under the ROC curve of 0.792.

Conclusions: The long-term hepatic outcomes of patients with Alagille syndrome can be predicted based on serum total bilirubin between the ages of 12-24 months combined with fibrosis on liver biopsy and the presence of xanthomata on physical examination.
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http://dx.doi.org/10.1111/liv.12920DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5401769PMC
May 2016

Exome sequencing reveals compound heterozygous mutations in ATP8B1 in a JAG1/NOTCH2 mutation-negative patient with clinically diagnosed Alagille syndrome.

Am J Med Genet A 2015 Apr 3;167A(4):891-3. Epub 2015 Mar 3.

Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.

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http://dx.doi.org/10.1002/ajmg.a.36946DOI Listing
April 2015

Moyamoya syndrome associated with Alagille syndrome: outcome after surgical revascularization.

J Pediatr 2015 Feb 30;166(2):470-3. Epub 2014 Oct 30.

Division of Gastroenterology, Hepatology, and Nutrition, The Hospital for Sick Children, Toronto, Ontario, Canada; University of Toronto, Toronto, Ontario, Canada. Electronic address:

Vasculopathy is well-described in Alagille syndrome (ALGS); however, few data exist regarding neurosurgical interventions. We report 5 children with ALGS with moyamoya who underwent revascularization surgery. Postsurgical complications included 1 stroke and 1 death from thalamic hemorrhage. Global function improved in survivors. Revascularization is reasonably safe in patients with ALGS and may improve neurologic outcomes.
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http://dx.doi.org/10.1016/j.jpeds.2014.10.067DOI Listing
February 2015

Incidence of perforation in pediatric GI endoscopy and colonoscopy: an 11-year experience.

Gastrointest Endosc 2013 Jun 20;77(6):960-6. Epub 2013 Feb 20.

Department of Pediatrics, University of Washington School of Medicine, Seattle Children's Hospital, Seattle, Washington 98115, USA.

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http://dx.doi.org/10.1016/j.gie.2012.12.020DOI Listing
June 2013

Pancreatic insufficiency is not a prevalent problem in Alagille syndrome.

J Pediatr Gastroenterol Nutr 2012 Nov;55(5):612-4

Hospital for Sick Children, Toronto, Canada.

Alagille syndrome (ALGS) is an inherited multisystem disorder in which pancreatic insufficiency (PI) has been regarded a minor but important clinical manifestation. As part of a multicenter prospective study, 42 patients with ALGS underwent fecal elastase (FE) measurement to screen for exocrine PI. FE measurements were normal (>200  μg/g) in 40 (95%) and indeterminate (100-200  μg/g) in 2 (5%). As FE is the most reliable screen for PI, these data suggest that PI is not a prevalent problem in ALGS.
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http://dx.doi.org/10.1097/MPG.0b013e31825eff61DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3666161PMC
November 2012

NOTCH2 mutations in Alagille syndrome.

J Med Genet 2012 Feb 29;49(2):138-44. Epub 2011 Dec 29.

Division of Gastroenterology and Nutrition, Department of Pediatrics, The Hospital for Sick Children and University of Toronto, Canada.

Background: Alagille syndrome (ALGS) is a dominant, multisystem disorder caused by mutations in the Jagged1 (JAG1) ligand in 94% of patients, and in the NOTCH2 receptor in <1%. There are only two NOTCH2 families reported to date. This study hypothesised that additional NOTCH2 mutations would be present in patients with clinical features of ALGS without a JAG1 mutation.

Methods: The study screened a cohort of JAG1-negative individuals with clinical features suggestive or diagnostic of ALGS for NOTCH2 mutations.

Results: Eight individuals with novel NOTCH2 mutations (six missense, one splicing, and one non-sense mutation) were identified. Three of these patients met classic criteria for ALGS and five patients only had a subset of features. The mutations were distributed across the extracellular (N=5) and intracellular domains (N=3) of the protein. Functional analysis of four missense, one nonsense, and one splicing mutation demonstrated decreased Notch signalling of these proteins. Subjects with NOTCH2 mutations demonstrated highly variable expressivity of the affected systems, as with JAG1 individuals. Liver involvement was universal in NOTCH2 probands and they had a similar prevalence of ophthalmologic and renal anomalies to JAG1 patients. There was a trend towards less cardiac involvement in the NOTCH2 group (60% vs 100% in JAG1). NOTCH2 (+) probands exhibited a significantly decreased penetrance of vertebral abnormalities (10%) and facial features (20%) when compared to the JAG1 (+) cohort.

Conclusions: This work confirms the importance of NOTCH2 as a second disease gene in ALGS and expands the repertoire of the NOTCH2 related disease phenotype.
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http://dx.doi.org/10.1136/jmedgenet-2011-100544DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3682659PMC
February 2012

Renal anomalies in Alagille syndrome: a disease-defining feature.

Am J Med Genet A 2012 Jan 21;158A(1):85-9. Epub 2011 Nov 21.

Division of Gastroenterology, Hepatology and Nutrition at The Hospital for Sick Children, Toronto, Ontario, Canada.

Alagille syndrome (ALGS) is an autosomal dominant condition, primarily caused by mutations in JAGGED1. ALGS is defined by cholestatic liver disease, cardiac disease and involvement of the face, skeleton, and eyes with variable expression of these features. Renal involvement has been reported though not formally described. The objective of this study was to systematically characterize the renal involvement in ALGS. We performed a retrospective review of 466 JAGGED1 mutation-positive ALGS patients. Charts were reviewed for serum biochemistries, renal ultrasounds or other imaging, urinalysis, and clinical reports from pediatric nephrologists. The clinical data were reviewed by two pediatric hepatologists and a pediatric nephrologist. Of 466 charts reviewed we found 187 yielded evaluable renal information. Of these, 73/187 were shown to have renal involvement, representing 39% of the study cohort. Renal dysplasia was the most common anomaly seen. Genotype analysis of the JAGGED1 mutations in the patients with and without renal involvement did not reveal an association with mutation type. From the study we concluded that renal involvement has a prevalence of 39% in ALGS in our evaluable patients. Renal dysplasia is the most common renal anomaly. This finding correlates with the known role of the Notch pathway in glomerular development. Since renal disease of the type seen in ALGS can impair growth and impact liver transplantation, there is a clear need for a prospective study of renal involvement in ALGS and the development of guidelines for evaluation and management. These data also suggest that renal involvement be considered the sixth defining criterion for ALGS.
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http://dx.doi.org/10.1002/ajmg.a.34369DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4511708PMC
January 2012

A novel method to enhance informed consent: a prospective and randomised trial of form-based versus electronic assisted informed consent in paediatric endoscopy.

J Med Ethics 2011 Apr 18;37(4):194-200. Epub 2011 Jan 18.

Division of Gastroenterology, Department of Pediatrics, Doernbecher Children's Hospital, Center for Ethics in Health Care, Oregon Health and Science University, 707 SW Gaines Street, Mailcode CDRCP, 707 SW Gaines Street, Portland, OR 97239, USA.

Objectives: To evaluate the adequacy of paediatric informed consent and its augmentation by a supplemental computer-based module in paediatric endoscopy.

Methods: The Consent-20 instrument was developed and piloted on 47 subjects. Subsequently, parents of 101 children undergoing first-time, diagnostic upper endoscopy performed under moderate IV sedation were prospectively and consecutively, blinded, randomised and enrolled into two groups that received either standard form-based informed consent or standard form-based informed consent plus a commercial (Emmi Solutions, Inc, Chicago, Il), sixth grade level, interactive learning module (electronic assisted consent). Anonymously and electronically, the subjects' anxiety (State Trait Anxiety Inventory), satisfaction (Modified Group Health Association of America), number of questions asked, and attainment of informed consent were assessed (Consent-20). Statistics were calculated using t test, paired t test, and Mann Whitney tests.

Results: The ability to achieve informed consent, as measured by the new instrument, was 10% in the control form-based consent group and 33% in the electronic assisted consent group (p<0.0001). Electronically assisting form-based informed consent did not alter secondary outcome measures of subject satisfaction, anxiety or number of questions asked in a paediatric endoscopy unit.

Conclusions: This study demonstrates the limitations of form-based informed consent methods for paediatric endoscopy. It also shows that even when necessary information was repeated electronically in a comprehensive and standardised video, informed consent as measured by our instrument was incompletely achieved. The supplemental information did, however, significantly improve understanding in a manner that did not negatively impact workflow, subject anxiety or subject satisfaction. Additional study of informed consent is required.
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http://dx.doi.org/10.1136/jme.2010.037622DOI Listing
April 2011

Medical management of Alagille syndrome.

J Pediatr Gastroenterol Nutr 2010 Jun;50(6):580-6

Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children, Toronto, Ontario, Canada.

Alagille syndrome is a highly variable, autosomal dominant disorder that affects the liver, heart, eyes, face, skeleton, kidneys, and vascular system. Much has been learned about the genetics of this disorder, which is caused primarily by mutations in the Notch signaling pathway ligand JAGGED1; however, the medical management of this condition is complex and continues to generate controversy. The significant variability of organ involvement requires the managing physician to have an understanding of the breadth and interplay of the variable manifestations. Furthermore, the liver disease in particular requires an appreciation of the natural history and evolution of the profound cholestasis.
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http://dx.doi.org/10.1097/MPG.0b013e3181d98ea8DOI Listing
June 2010

Pathologic lower extremity fractures in children with Alagille syndrome.

J Pediatr Gastroenterol Nutr 2010 Jul;51(1):66-70

Department of Pediatrics, The Department of Biostatistics and Epidemiology at the University of Pennsylvania School of Medicine, Philadelphia, PA, USA.

Objectives: : In this retrospective study, we aimed to determine the incidence and distribution of fractures in patients with Alagille syndrome, 1 of the leading inherited causes of pediatric cholestatic liver disease.

Materials And Methods: : Surveys regarding growth, nutrition, and organ involvement were distributed to patient families in the Alagille Syndrome Alliance of the Children's Hospital of Philadelphia research database. Patients with a history of fracture were identified by their response to 1 question, and details characterizing each patient's medical, growth, and fracture history were obtained through chart review and telephone contact.

Results: : Twelve of 42 patients (28%) reported a total of 27 fractures. Patients experienced fractures at a mean age of 5 years, which contrasts with healthy children, in whom fracture incidence peaks in adolescence. Fractures occurred primarily in the lower extremity long bones (70%) and with little or no trauma (84%). Estimated incidence rate calculations yielded 399.6 total fractures per 10,000 person-years (95% confidence interval 206.5, 698.0) and 127.6 femur fractures per 10,000 person-years (95% confidence interval 42.4, 297.7). There were no differences in sex, age distribution, or organ system involvement between the fracture and no-fracture groups.

Conclusions: : Children with Alagille syndrome may be at risk for pathologic fractures, which manifest at an early age and in a unique distribution favoring the lower extremity long bones. Although this preliminary study is limited by small sample size and potential ascertainment bias, the data suggest that larger studies are warranted to further characterize fracture risk and explore factors contributing to bone fragility in these children.
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http://dx.doi.org/10.1097/MPG.0b013e3181cb9629DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2893241PMC
July 2010