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Chapter 14 - Alagille Syndrome
- from Section II - Cholestatic Liver Disease
- Edited by Frederick J. Suchy, Ronald J. Sokol, William F. Balistreri
- Edited in association with Jorge A. Bezerra, Cara L. Mack, Benjamin L. Shneider
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- Book:
- Liver Disease in Children
- Published online:
- 19 January 2021
- Print publication:
- 18 March 2021, pp 222-241
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Summary
Alagille syndrome (ALGS) is an autosomal dominant, multisystem disorder which was first described in 1969 by Daniel Alagille as a constellation of clinical features in five different organ systems [1]. The diagnosis was based on the presence of intrahepatic bile duct paucity on liver biopsy in association with at least three of the major clinical features: chronic cholestasis, cardiac disease (most often peripheral pulmonary stenosis), skeletal abnormalities (typically butterfly vertebrae), ocular abnormalities (primarily posterior embryotoxon), and characteristic facial features. Advances in molecular diagnostics have enabled an appreciation of the broader disease phenotype with recognition of renal and vascular involvement [2, 3]. There is significant variability in the extent to which each of these systems is affected in an individual, if at all [4, 5]. ALGS was originally estimated to have a frequency of one in 70,000 live births, though this was based on the presence of neonatal cholestasis. However, this is clearly an underestimate as molecular testing has demonstrated that many individuals with a disease-causing mutation do not have neonatal liver disease and the true frequency is likely closer to one in 30,000 [5].
Chapter 14 - Alagille syndrome
- from Section II - Cholestatic liver disease
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- By Binita M. Kamath, Department of Paediatrics, University of Toronto; Division of Gastroenterology, Hepatology and Nutrition, Hospital for Sick Children, Toronto, Ontario, Canada, Nancy B. Spinner, Division of Genomic Diagnostics, and Evelyn Willing Bromley Chair of Pediatric Pathology, Department of Pathology Perelman School of Medicine at the University of Pennsylvania, Children’s Hospital of Pennsylvania, Pittsburgh, PA, USA, David A. Piccoli, Division of Gastroenterology, Hepatology and Nutrition, Fred and Suzanne Biesecker Professor of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Children’s Hospital of Pennsylvania, Philadelphia, PA, USA
- Edited by Frederick J. Suchy, University of Colorado Medical Center, Ronald J. Sokol, University of Colorado Medical Center, William F. Balistreri
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- Book:
- Liver Disease in Children
- Published online:
- 05 March 2014
- Print publication:
- 20 February 2014, pp 216-233
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Summary
Introduction
Alagille syndrome (ALGS) is an autosomal dominant, multisystem disorder which was first described in 1969 by Daniel Alagille as a constellation of clinical features in five different organ systems [1]. The diagnosis was based on the presence of intrahepatic bile duct paucity on liver biopsy in association with at least three of the major clinical features: chronic cholestasis, cardiac disease (most often peripheral pulmonary stenosis), skeletal abnormalities (typically butterfly vertebrae), ocular abnormalities (primarily posterior embryotoxon), and characteristic facial features. Advances in molecular diagnostics have enabled an appreciation of the broader disease phenotype with recognition of renal and vascular involvement [2,3]. There is significant variability in the extent to which each of these systems is affected in an individual, if at all [4,5]. It was originally estimated that ALGS had a frequency of 1 in 70000 live births, although this was based on the presence of neonatal cholestasis. However, this is clearly an underestimate as molecular testing has demonstrated that many individuals with a disease-causing mutation do not have neonatal liver disease and the true frequency is likely closer to 1 in 30000 [5].
Alagille syndrome is caused by mutations in JAGGED1 (JAG1), encoding a ligand Jagged1 in the Notch signaling pathway [6,7]. Mutations in JAG1 are identified in 94% of clinically defined probands [8]. Recently, mutations in NOTCH2 have been identified in a few patients with ALGS who do not have JAG1 mutations [9]. This exciting development has enhanced our understanding of the heterogeneity of this disorder, although much remains to be understood about the tremendous variability seen in affected individuals and the likely genetic modifiers involved.
15 - Alagille Syndrome
- from SECTION II - CHOLESTATIC LIVER DISEASES
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- By Binita M. Kamath, M.B. B.Chir., Assistant Professor of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania; Attending Physician, Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, Nancy B. Spinner, Ph.D., Professor of Human Genetics in Pediatrics, Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania; Director, Cytogenetics Laboratory, Department of Pathology and Clinical Laboratories, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, David A. Piccoli, M.D., Biesecker Professor of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania; Chief, Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
- Edited by Frederick J. Suchy, Mount Sinai School of Medicine, New York, Ronald J. Sokol, University of Colorado, Denver, William F. Balistreri, University of Cincinnati
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- Book:
- Liver Disease in Children
- Published online:
- 18 December 2009
- Print publication:
- 07 May 2007, pp 326-345
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Summary
Alagille syndrome (AGS) is a highly variable, multisystem, autosomal dominant disorder that primarily affects the liver, heart, eyes, face, and skeleton [1–3]. There is significant variability in the extent to which each of these systems is affected in an individual, if at all [4, 5]. AGS has traditionally been diagnosed based on the presence of intrahepatic bile duct paucity on liver biopsy in association with at least three of the major clinical features: chronic cholestasis, cardiac disease (most often peripheral pulmonary stenosis), skeletal abnormalities (typically butterfly vertebrae), ocular abnormalities (primarily posterior embryotoxon), and characteristic facial features [6]. It has an estimated frequency of 1 in 70,000 live births based on the presence of neonatal cholestasis. However, this is an underestimate as molecular testing has demonstrated that many individuals with a disease-causing mutation do not have neonatal liver disease.
Alagille syndrome is caused by mutations in Jagged1 (JAG1), a ligand in the Notch signaling pathway [7, 8]. JAG1 mutations are identified in more than 90% of clinically diagnosed probands [9]. Recently, mutations in Notch2 have been identified in a few patients with AGS who do not have JAG1 mutations [10]. This exciting development has enhanced our understanding of the heterogeneity of this disorder, though much remains to be understood about the tremendous variability seen in affected individuals and the likely genetic modifiers involved.
BILE DUCT PAUCITY
Bile duct paucity is present in a diverse group of metabolic, infectious, and inflammatory hepatic disorders in infancy.