Liver disease Chronic cholestasis occurs in a very high proportion (95%) of cases, and most commonly, presents in the neonatal period or first 3 months of life, with jaundice due to conjugated hyperbilirubinemia. Serum bile acids and liver function tests are raised, pruritus and growth failure may occur, and xanthomas may be present. The liver biopsy typically shows a paucity of the intrahepatic bile ducts, though in the newborn ductal proliferation may occasionally be seen, usually with portal inflammation, which may lead to a misdiagnosis of biliary atresia. This is important, because biliary atresia patients may undergo the Kasai procedure, which is not beneficial in ALGS. Heart disease There is evidence of cardiovascular anomalies in more than 90% of ALGS subjects. Involvement of the pulmonary outflow tract is the most common type of congenital heart disease, with some form of peripheral pulmonary stenosis (PPS) affecting at least two-thirds of cases. Tetralogy of Fallot (TOF) is the most common complex structural anomaly, occurring in up to 16% of cases. Other malformations include ventricular septal defect, atrial septal defect, aortic stenosis, and coarctation of the aorta, and hypoplastic left heart syndrome has been reported in one patient with a 20p12 deletion. Congenital heart disease may be the sole manifestation of ALGS if the condition is defined by a positive genotype Ophthalmic features Posterior embryotoxon, the most common ophthalmic feature of ALGS has been reported in up to 90% of patients. This is the prominence of the centrally positioned Schwalbe’s ring (or line) at the point where the corneal endothelium and the uveal trabecular meshwork join. However, this also occurs in up to 15% of the normal population, as well as nearly 70% of patients with deletion 22q11 syndrome. A wide variety of ophthalmic abnormalities may be seen in ALGS affecting the cornea, iris, retina, and optic disk. Axenfeld anomaly, a prominent Schwalbe’s ring with attached iris strands, is seen in 13% of ALGS patients, an unusual mosaic pattern of iris stromal hypoplasia, microcornea, keratoconus, congenital macular dystrophy, shallow anterior chamber, exotropia, band keratopathy, and cataracts. Skeletal anomalies  A characteristic form of segmentation anomaly known as ‘butterfly’ vertebrae may occur in at least 80% of cases. This consists of a sagittal cleft in one or more thoracic vertebrae, visible on an antero-posterior radiograph, and is due to failure of fusion of the anterior vertebral arches. Vertebral segmentation anomalies occur in a wide range of disorders22 but, with the exception of deletion 22q11 syndrome (again), the relatively symmetrical ‘butterfly’ appearance is unusual.

The face It is well reported that children with ALGS have mild but recognisable dysmorphic features including a prominent forehead, deep-set eyes with moderate hypertelorism, upslanting palpebral fissures, depressed nasal bridge, straight nose with a bulbous tip, large ears, prominent mandible, and pointed chin.28 In some children, the shape of the face is strikingly triangular. Vascular events  Vascular accidents have been reported to occur in up to 15% of cases,10 and were a cause of death in 34% in one series.29 Intracranial bleeding may occur as a consequence of relatively minor head trauma. Studies have identified anomalies of the basilar, carotid, and middle cerebral arteries and renovascular anomalies, middle aortic syndrome, and Moyamoya syndrome have all been reported. Learning difficulties Early studies highlighted a relatively high frequency of mental retardation,8 but this may have represented ascertainment bias.