Alagille syndrome : An Overview

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. The syndrome has recently 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. A minority (6-7%) of patients have complete deletion of JAG1, and approximately 15-50% of mutations are spontaneous.

Clinical

Physical

Presentation varies. Some patients are diagnosed after prolonged neonatal jaundice or when liver biopsy findings reveal paucity of intrahepatic bile ducts. Others may be diagnosed during evaluation for right-sided heart disease. Some individuals are diagnosed by careful examination after an index case is identified in the family.

• Nutrition and growth
  • Children often present with poor linear growth.
  • Altered longitudinal growth is attributed to wasting or inadequate intake, and an element of growth hormone resistance may also be present.⁶ Studies to assess the impact of higher doses of growth hormone on linear growth in patients with Alagille syndrome are currently underway.
• Head and neck
  • Commonly associated facial features include broadened forehead, pointed chin, and elongated nose with bulbous tip.
  • Characteristic facial features may not be obvious during infancy but may become more apparent as the child ages.
• Ophthalmologic
  • Ocular abnormalities are common.⁷ The most frequent ophthalmologic finding is a posterior embryotoxon, which was observed in more than 75% of patients in one large series conducted by Emerick et al.⁸
  • Some of these patients may also have the Axenfeld anomaly (ie, iris attachment to Descemet membrane).
  • Other findings reported include retinitis pigmentosa, pupillary abnormalities, and anomalies of the optic disc.
• Cardiovascular
  • Nearly all patients have cardiac murmurs.
  • The most common cardiac lesions are stenoses within the pulmonary tree (peripheral pulmonic stenosis) with or without other structural lesions.
  • Hemodynamically significant lesions include atrial septal defect (ASD), ventricular septal defect (VSD), tetralogy of Fallot, patent ductus arteriosus (PDA), and pulmonary atresia (PA). Significant intracardiac lesions place patients with Alagille syndrome at increased mortality risk.
• Hepatic
  • Hepatic disease is a key feature of Alagille syndrome.
  • Most infants present with cholestatic jaundice.
  • Hepatosplenomegaly is common.
  • Elevations in serum bile acids often result in severe pruritus and xanthomas (hypercholesterolemia).
  • Fat-soluble vitamin deficiencies, including coagulopathies and rickets, are frequent.
• Skeletal
  • Abnormalities of the vertebrae, ribs, and hands are frequently associated with Alagille syndrome.
  • Butterfly hemivertebrae were found in one half of the patients analyzed by Emerick et al in a large series of patients with Alagille syndrome.⁸
  • Other isolated anomalies include rib anomalies and shortening of the radius, ulna, and phalanges.
• Neurologic
  • Mild developmental delay and mental retardation are reported in some children with Alagille syndrome.
  • If noted during the physical examination, diminished deep tendon reflexes should direct the clinician to exclude vitamin E deficiency.
• Renal: Occult renal artery stenosis, lipoid nephrosis, or glomerulosclerosis may present with signs and symptoms of chronic hypertension.
• Vascular: Vascular lesions have been recently described in 6% of the patients with confirmed Alagille syndrome who were followed by Kamath et al.⁹ These lesions included basilar artery aneurysms, internal carotid artery anomalies, middle cerebral artery aneurysm, Moyamoya disease and aortic aneurysms,coarctation of the aorta, and renal artery stenosis.

Causes

• Alagille syndrome is an autosomal dominant mutation with variable expression localized to the JAG1 gene (20p12).
• The JAG1 gene product functions as a ligand for the notch-1 receptor. In animal models, interactions between JAG1 ligand and notch-1 receptor play an important role in the determination of ultimate cell fate. Few patients, generally those with more severe phenotypes, have complete deletion of the JAG1 gene.