eMedicine Specialties > Pediatrics: General Medicine > Gastroenterology
Alagille Syndrome
Updated: Oct 22, 2009
Introduction
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
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 A minority (6-7%) of patients have complete deletion of JAG1, and approximately 15-50% of mutations are spontaneous.
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.
Clinical
Physical
Presentation of Alagille syndrome (AS) 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.7 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.8 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.9
- 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.
- Recent data has reported an association between Wolff-Parkinson-White syndrome in a subset of patients with Alagille syndrome.10
- 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.9
- 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.11 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.
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| References |
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References
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Watson GH, Miller V. Arteriohepatic dysplasia: familial pulmonary arterial stenosis with neonatal liver disease. Arch Dis Child. Jun 1973;48(6):459-66. [Medline].
Alagille D, Odievre M, Gautier M, Dommergues JP. Hepatic ductular hypoplasia associated with characteristic facies, vertebral malformations, retarded physical, mental, and sexual development, and cardiac murmur. J Pediatr. Jan 1975;86(1):63-71. [Medline].
McDaniell R, Warthen DM, Sanchez-Lara PA, et al. NOTCH2 mutations cause Alagille syndrome, a heterogeneous disorder of the notch signaling pathway. Am J Hum Genet. Jul 2006;79(1):169-73. [Medline].
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Further Reading
Keywords
Alagille syndrome, AS, Alagille's syndrome, Alagille-Watson syndrome, arteriohepatic dysplasia, syndromic bile duct paucity, pulmonary valvular stenosis, hypoplasia of the hepatic ducts, mental retardation, treatment, diagnosis


Overview: Alagille Syndrome