Alagille syndrome: pathogenesis, diagnosis and management

Abstract

Alagille syndrome (ALGS), also known as arteriohepatic dysplasia, is a multisystem disorder due to defects in components of the Notch signalling pathway, most commonly due to mutation in JAG1 (ALGS type 1), but in a small proportion of cases mutation in NOTCH2 (ALGS type 2). The main clinical and pathological features are chronic cholestasis due to paucity of intrahepatic bile ducts, peripheral pulmonary artery stenosis, minor vertebral segmentation anomalies, characteristic facies, posterior embryotoxon/anterior segment abnormalities, pigmentary retinopathy, and dysplastic kidneys. It follows autosomal dominant inheritance, but reduced penetrance and variable expression are common in this disorder, and somatic/germline mosaicism may also be relatively frequent. This review discusses the clinical features of ALGS, including long-term complications, the clinical and molecular diagnosis, and management.

Figure 1

Posterior embryotoxon (arrowed). Courtesy of Mr Anthony Quinn.

Figure 2

Butterfly vertebrae seen in the thoracic and upper lumbar regions. The child had undergone cardiac surgery, hence the presence of visible wires.

Figure 3

The hands of the child shown in Figure 4a. The digits are generally fusiform in shape and the terminal phalanges somewhat hypoplastic. Courtesy of Dr Peter Lunt.

Figure 4

Two children, (a) and (b) with AGS. Both manifest deep-set eyes, a broad nasal root, and prominent chin. The palpebral fissures are not upslanting, and hypertelorism does not appear to be present. Courtesy of Drs Peter Lunt, Alison Male, and Simon Holden.

Figure 5

Two children, (a) and (b), and an adult, (c), with ALGS. None of the three have deep-set eyes, but their palpebral fissures are obviously upslanting and narrow. They possibly have a degree of hypertelorism. Courtesy of Drs Daniela Pilz, Carole Brewer, and Mr Alan Hardie. (b) Is reproduced by kind permission of Elsevier; the image is published as Figure 6.5A in Emery's Elements of Medical Genetics, 14th edition, Turnpenny and Ellard.

Figure 6

Flow diagram of genetic investigations and management for suspected ALGS patients.