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Published in Samar Razaq, Difficult Cases in Primary Care, 2021
Alagille’s syndrome is an autosomal dominant disorder in which there is paucity of the intrahepatic bile ducts. The resultant chronic cholestasis causes jaundice, pruritis and hypercholesterolemia. Dysmorphic faces, cardiac anomalies, vertebral anomalies, failure to thrive and developmental delay are features of the syndrome. Budd–Chiari’s syndrome is a rare condition in which there is obstruction of the hepatic veins. Gilbert’s syndrome is a usually harmless condition in which reduced levels of a particular enzyme (uridine-diphosphate glucuronosyltransferase) in the liver results in slightly raised serum bilirubin levels. Criggler–Najjar’s syndrome is a rare disorder in which a defective enzyme results in defective breakdown of bile, causing its levels to rise.
Gastroenterology
Published in Stephan Strobel, Lewis Spitz, Stephen D. Marks, Great Ormond Street Handbook of Paediatrics, 2019
Alagille syndrome sually presents in the first 2 years of life. Typical facial features of deep set eyes, straight nose, pointed chin and wide forehead are not usually recognisable until older. There is intrahepatic bile duct paucity and vascular anomalies. Other abnormalities may occur in the development of the heart (most commonly pulmonary stenosis), eyes, vertebrae and the craniofacial region.
Microdeletion Syndromes
Published in Merlin G. Butler, F. John Meaney, Genetics of Developmental Disabilities, 2019
Gopalrao V. N. Velagaleti, Nancy J. Carpenter
Information can be obtained online through computer searches of key words or syndrome names. Parent or family support groups are also available for most syndromes or disorders. The following is a list of organizations or support groups where pertinent information about this syndrome can be found: Alagille Syndrome Alliance.American Liver Foundation: www.liverfoundation.org.
Central Hepatic Regenerative Nodules in Alagille Syndrome: A Clinicopathological Review
Published in Fetal and Pediatric Pathology, 2021
The characteristic liver pathology in Alagille syndrome is interlobular bile duct paucity. Alagille [2] describes a ratio of the number of interlobular bile ducts to the number of portal tracts of less than 0.4 and recommends examining at least 10 portal tracts to derive this ratio. This paucity of bile ducts increases after infancy and has been reported in 60% of infants versus 95% of older patients [4]. Additional features often seen in Alagille syndrome patients include cholestasis, portal inflammation and fibrosis [2, 4]. Emerick et al. [4] report progression to bridging fibrosis in 48% of patients with fibrosis on their initial biopsy and cirrhosis in an additional 26% of patients in this subgroup. In cirrhotic patients, the paucity of interlobular bile ducts is well established and usually without a significant ductular reaction (Fig. 1A,B). Lobular cholestatic changes are variably seen. Cytokeratin 7 immunohistochemical stain can be helpful to highlight bile duct loss and aberrant cytokeratin 7 expression in the lobular hepatocytes (Fig. 1C). Similar to other cholestatic liver disorders, copper deposition is frequently identified in the periportal hepatocytes (Fig. 1D).
The Notch pathway: a novel therapeutic target for cardiovascular diseases?
Published in Expert Opinion on Therapeutic Targets, 2019
Giorgio Aquila, Aleksandra Kostina, Francesco Vieceli Dalla Sega, Eugeniy Shlyakhto, Anna Kostareva, Luisa Marracino, Roberto Ferrari, Paola Rizzo, Anna Malaschicheva
A recent study of a cohort of 428 patients with a spectrum of diseases affecting aortic development such as aortic valve stenosis, a bicuspid aortic valve, aortic valve insufficiency coarctation of the aorta, and hypoplastic left heart syndrome, subvalvular or supravalvular aortic stenosis, hypoplastic aortic arch, interruption of the aorta, and mitral valve anomalies clearly demonstrates that the phenotypic spectrum of NOTCH1 mutations includes a wide variety of pathologies affecting the whole conotruncus of the heart [45]. This is in agreement with the described role of the Notch pathway in determining the fate of neural crest–derived cells. Alagille syndrome (ALGS), a congenital disease that mainly affects liver ducts and heart development, in the vast majority (up to 96%) of patients, is caused by mutations in JAGGED1 and NOTCH2 (in 1–2% of the cases) [46].
Unexplained cholestasis in adults and adolescents: diagnostic benefit of genetic examination
Published in Scandinavian Journal of Gastroenterology, 2018
Luise Aamann, Nikolaj Ørntoft, Ida Vogel, Henning Grønbaek, Naja Becher, Hendrik Vilstrup, Peter Ott, Dorte Launholt Lildballe
Some very rare pediatric cholestatic diseases are caused by identified autosomal recessively inherited mutations in genes associated with hepatic bile acid transport (Table 1) [1–6]. Recent studies suggest that some of the mutations that cause pediatric cholestatic disease in the homozygous form, can cause cholestatic disease in adults even in a heterozygous form (Table 1). This unlocks the possibility that genetic cholestatic disease in adulthood could be more common than in children in which case genetic examination in the adult population would be an important add-on to our standard diagnostic work-up. Additionally, JAG1 and NOTCH2 mutations may cause Alagille syndrome in a dominant fashion with variable penetrance. UGT1A1 is only involved in bilirubin conjugation and sequencing of UGT1A1. Mutations may lead to Gilbert or Crigler–Najjar syndromes with hyperbilirubinemia, but not cholestasis. However, since casuistic reports suggest that rare cases may be associated with cholestasis, UGT1A1 was included in the panel [7,8].