Arteriohepatic Dysplasia: A Benign Syndrome of Intrahepatic Cholestasis with Multiple Organ Involvement

Riely, Caroline A.; Cotlier, Edward; Jensen, Pamela S.; Klatskin, Gerald

doi:10.7326/0003-4819-91-4-520

Cited by 115 publications

(54 citation statements)

References 28 publications

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“…Notch2 deficiency leads to bile duct agenesis perinatally and secondary bile duct formation after weaning (Falix et al, 2014), a process that appears to be Notch independent (Walter et al, 2014). A similar recovery of the liver phenotype with age has been reported in individuals with Alagille syndrome (Riely et al, 1979), although it is not yet clear which JAG1 or NOTCH2 genotypes, if any, are linked to recovery.…”

Section: Notch2 and Jag1 Function In The Livermentioning

confidence: 73%

The developmental biology of genetic Notch disorders

2017

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Notch signaling regulates a vast array of crucial developmental processes. It is therefore not surprising that mutations in genes encoding Notch receptors or ligands lead to a variety of congenital disorders in humans. For example, loss of function of Notch results in Adams-Oliver syndrome, Alagille syndrome, spondylocostal dysostosis and congenital heart disorders, while Notch gain of function results in Hajdu-Cheney syndrome, serpentine fibula polycystic kidney syndrome, infantile myofibromatosis and lateral meningocele syndrome. Furthermore, structure-abrogating mutations in NOTCH3 result in CADASIL. Here, we discuss these human congenital disorders in the context of known roles for Notch signaling during development. Drawing on recent analyses by the exome aggregation consortium (EXAC) and on recent studies of Notch signaling in model organisms, we further highlight additional Notch receptors or ligands that are likely to be involved in human genetic diseases.

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Section: Notch2 and Jag1 Function In The Livermentioning

confidence: 73%

The developmental biology of genetic Notch disorders

2017

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“…The familial nature of this syndrome has been noted before but there is no agreement on the mode of transmission. In some families, the pedigree has suggested an autosomal dominant pattern (7,16,17) but in others, a recessive mode is more likely since parents are not affected (4).…”

Section: Discussionmentioning

confidence: 99%

Arteriohepatic Dysplasia in Infancy and Childhood: A Longitudinal Study of Six Patients

et al. 1982

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Arteriohepatic dysplasia (syndromatic ductular hypoplasia, Alagille syndrome) is a condition of chronic cholestasis dating from infancy accompanied by characteristic facies, pulmonic stenosis, and other somatic abnormalities. The pathologic hallmark of arteriohepatic dysplasia is a paucity or absence of intrahepatic bile ducts, wildely regarded as a congenital deficiency. We present a longitudinal study of six infants and children with arteriohepatic dysplasia, stressing evolution of the characteristic pathology on liver biopsy. All patients were biopsied twice. All five liver biopsies performed during infancy (<6 months old) showed intrahepatic cholestasis and portal inflammation, and two infants had, in addition, giant cell transformation. No infant showed congenital absence of interlobular bile ducts. Three of five infants had normal numbers of interlobular bile ducts (0.5 to 1.0 interlobular bile ducts per triad) and two infants had a paucity of interlobular bile ducts (<0.5 per triad). Three infants showed focal destructive inflammation of interlobular bile ducts. All biopsies performed later in childhood, between 3 and 20 years of age, showed a paucity or absence of interlobular bile ducts. At this time cholestasis and inflammation had largely resolved but some fibrosis persisted. The number of interlobular bile ducts decreased with age in each patient but there was no characteristic age at which interlobular bile ducts disappeared completely. The presence of interlobular bile ducts in infancy followed later in childhood by paucity or absence of interlobular bile ducts, suggests that intrahepatic bile duct deficiency in some patients with arteriohepatic dysplasia is acquired rather than congenital. The mechanism of bile duct disappearance in these patients may have been destructive inflammation of duct epithelium. Histopathologic diagnosis of arteriohepatic dysplasia may be difficult or impossible in infancy since interlobular bile ducts may be present at that time. However, arteriohepatic dysplasia should be considered in the differential diagnosis of all infants with cholestasis and such infants should have careful clinical evaluation for the syndromatic features of arteriohepatic dysplasia. Evaluation of their liver biopsies should include specific morphometric assessment of interlobular bile ducts.

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“…Alagille syndrome, a familial autosomal dominant disorder, most commonly presents with neonatal cholestasis caused by intrahepatic biliary hypoplasia [1,7]. Hepatic and cardiac abnormalities are the most common causes of death, as seen in our cases.…”

Section: Discussionmentioning

confidence: 78%

“…It is caused by mutation in the Jagged 1 (JAG1) gene of the NOTCH pathway [1,2]. In 1975, Alagille and associates [3] first described the systemic abnormalities of Alagille syndrome, including pulmonary artery hypoplasia, pale skin and hair, characteristic triangular facies, butterfly vertebral arches, intellectual disability, and growth retardation.…”

Section: Introductionmentioning

confidence: 99%

Anterior Chamber Pathology in Alagille Syndrome

Levin

Anninger

et al. 2016

Ocul Oncol Pathol

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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 Jagged 1 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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Arteriohepatic Dysplasia: A Benign Syndrome of Intrahepatic Cholestasis with Multiple Organ Involvement

Cited by 115 publications

References 28 publications

The developmental biology of genetic Notch disorders

The developmental biology of genetic Notch disorders

Arteriohepatic Dysplasia in Infancy and Childhood: A Longitudinal Study of Six Patients

Anterior Chamber Pathology in Alagille Syndrome

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