Alagille Syndrome

Updated: Jan 10, 2016
  • Author: Ann Scheimann, MD, MBA; Chief Editor: Carmen Cuffari, MD  more...
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Overview

Background

Alagille syndrome (AS) is an autosomal dominant disorder (OMIM 118450) associated with abnormalities of the liver, heart, skeleton, eye, and kidneys and a characteristic facial appearance. [1] In 1973, Watson and Miller reported 9 cases of neonatal liver disease with familial pulmonary valvular stenosis. [2] Then in 1975, Alagille et al described several patients with hypoplasia of the hepatic ducts with associated features. [3] Typical facial features are shown in the image below.

Typical facial features of Alagille syndrome. Note Typical facial features of Alagille syndrome. Note broad forehead, deep-set eyes and pointed chin. Courtesy of University of Washington, Seattle (Pagon RA, Adam MP, Ardinger HH, et al, Eds. Seattle (WA): University of Washington, Seattle; 1993-2014. Available at: www.ncbi.nlm.nih.gov/books/NBK1116/).
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Pathophysiology

Alagille syndrome is an autosomal dominant disorder with variable expression. Associated abnormalities include those of the liver, heart, eye, skeleton, and kidneys and characteristic facial features. Mild-to-moderate mental retardation also may be present. Mutations in either jagged-1 (JAG1) or notch-2 (NOTCH2) have been reported in patients with Alagille syndrome. [4, 5] The syndrome has been mapped to the 20p12-jagged-1 locus, JAG1, which encodes a ligand critical to the notch gene–signaling cascade that is important in fetal development. [6, 5] Notch signaling has been found to regulate formation of 3-dimensional intrahepatic biliary architecture in murine models. [7] A minority (6-7%) of patients have complete deletion of JAG1, and approximately 15-50% of mutations are spontaneous.

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Epidemiology

Frequency

United States

The incidence rate is approximately 1 case in every 100,000 live births.

Mortality/Morbidity

Major contributors to morbidity arise from bile duct paucity or cholestatic liver disease, underlying cardiac disease, CNS vasculopathy, Moyamoya disease, and renal disease.

Sex

No difference in penetrance is reported.

Age

Most children are evaluated when younger than 6 months for either neonatal jaundice (70%), or cardiac murmurs and symptoms (17%). Patients who are less affected, such as family members, are often diagnosed after an index case.

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