This autosomal dominant multisystem disorder affects primarily the liver with a paucity of intrahepatic bile ducts and cholestasis, but also includes cardiac, ocular and skeletal anomalies, and a typical facial appearance.
Cardiovertebral Syndrome; Alagille-Watson Syndrome; Watson-Miller Syndrome; Arteriohepatic Dysplasia (AHD); Cholestasis-Peripheral Pulmonary Stenosis; Hepatic Ductular Hypoplasia-Multiple Malformations Syndrome; Hepatofacioneuro-Cardiovertebral Syndrome.
Named after the French pediatrician Daniel Alagille (1925-2005) who described the disease together with his colleagues initially in 1969 in 25 patients and again in 1975 in 15 patients. However, the first publication was by the American pediatrician David W. Smith and colleagues who reported two siblings with AS. The British physicians Geoffrey H. Watson and V. Miller described the disease in five families in 1973.
Estimated in the range of 1:30,000 to 1:70,000 live births.
Autosomal dominant with incomplete penetrance and highly variable expression even within the same family with a possible range from basically asymptomatic gene carriers all the way to lethality due to severe cardiac or end-stage liver disease. However, 15 to 50% of cases are new mutations. In approximately 90% of patients AS is caused by mutations in the Jagged1 (JAG1) gene, which has been mapped to chromosome 20p12.2 (sometimes referred to as AS 1). In 5 to 7% of affected patients, exon and whole-gene deletions, including microdeletion of 20p12 can be detected. In a very small proportion of patients, the mutations responsible for AS have been located in the NOTCH2 gene mapped to chromosome band 1p12 (referred to as AS 2). The JAG1 and NOTCH2 genes encode for proteins involved in the Notch signaling pathway amongst neighboring cells and determine cell proliferation, cell fate, differentiation, and cell death during embryonic development. The lack of this information exchange results in the typical defects found in AS. Clinically, AS 1 and AS 2 are indistinguishable.
Mainly based on the characteristic clinical findings, but due to the wide spectrum of manifestations in this disease, the diagnosis is not always straightforward. Diagnostic criteria include a liver biopsy with histologic confirmation of bile duct paucity, which might not yet be present in infancy, even in patients eventually shown to have AS. The bile duct paucity seems to be progressive, and is probably more common later in infancy than in early life. Follow-up liver biopsies found bile duct paucity was present in 60% of infants younger than 6 months of age, while it was present in 95% of patients older than 6 months. Overall, intrahepatic bile duct paucity is present in 70 to 85% of patients. However, a liver biopsy is no longer mandatory if cholestasis is present. The diagnosis further requires three of the following five major clinical features: (1) Cholestasis; (2) A cardiac defect (typically peripheral ...