Practice Essentials

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]Typical facial features are shown in the image below.

Typical facial features of Alagille syndrome. Note broad forehead, deep-set eyes and pointed chin. Courtesy of University of Washington, Seattle (Pagon RA, Adam MP, Ardinger HH, et al, Eds. Seattle (WA): University of Washington, Seattle; 1993-2014. Available at: www.ncbi.nlm.nih.gov/books/NBK1116/).

Signs and symptoms of Alagille syndrome

The presentation of Alagille syndrome varies. Clinical features may include the following:

Poor linear growth
Characteristic facial features: Broadened forehead, pointed chin, and elongated nose with bulbous tip
Ocular abnormalities: The most frequent is a posterior embryotoxon; other findings reported include retinitis pigmentosa, pupillary abnormalities, and anomalies of the optic disc
Cardiovascular abnormalities: Cardiac murmurs, peripheral pulmonic stenosis, atrial septal defect, ventricular septal defect, tetralogy of Fallot, patent ductus arteriosus, and pulmonary atresia
Hepatic disorders: Cholestatic jaundice and hepatosplenomegaly
Severe pruritus (secondary to increased bile acids caused by cholestatic jaundice)
Xanthomas (secondary to hypercholesterolemia)
Fat-soluble vitamin deficiencies, including coagulopathies and rickets
Skeletal abnormalities of the vertebrae, ribs, and hands
Mild developmental delay and intellectual disability in some children
Renal disorders: Occult renal artery stenosis, lipoid nephrosis, and glomerulosclerosis
Vascular lesions: Basilar artery aneurysms, internal carotid artery anomalies, middle cerebral artery aneurysm, Moyamoya disease and aortic aneurysms, coarctation of the aorta, and renal artery stenosis

See Presentation for more detail.

Diagnosis of Alagille syndrome

Chromosomal analysis for mutations within the JAG1 gene (20p12) confirms the diagnosis of Alagille syndrome.

Laboratory studies

The following laboratory abnormalities are commonly observed in patients with Alagille syndrome:

Abnormalities of liver function
Fat-soluble vitamin deficiencies
Prolongation of prothrombin time (PT) or activated partial thromboplastin time (aPTT)
Hypercholesterolemia
Elevation of bilirubin levels during infancy
Elevated serum bile acid levels

Imaging studies

The following imaging studies are useful in the workup:

Abdominal ultrasonography to screen for renal anomalies
Ultrasonography in older patients to screen for hepatoma or hepatocellular carcinoma
Spinal radiographs to screen for vertebral anomalies

See Workup for more detail.

Management of Alagille syndrome

Correction of vitamin deficiencies is important for optimal growth and development. Bile acid–induced pruritus is often recalcitrant to medical therapy and significantly affects quality of life. Agents that have been helpful in some patients include hydroxyzine, diphenhydramine, cholestyramine, and rifampin. All patients, except those with peripheral pulmonic stenosis, require subacute bacterial endocarditis prophylaxis.

Surgical management for bile acid–induced pruritus includes biliary diversion and eventual orthotopic liver transplantation for those with refractory disease. Indications for consideration of liver transplantation include the following:

Progressive hepatic dysfunction
Severe portal hypertension
Failure to thrive
Intractable pruritus and osteodystrophy

See Treatment and Medication for more detail.

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 intellectual disability 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]}Notch signaling has been found to regulate formation of 3-dimensional intrahepatic biliary architecture in murine models.^[7]A minority (6-7%) of patients have complete deletion of JAG1, and approximately 15-50% of mutations are spontaneous.

Etiology

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.

United States statistics

The incidence rate is approximately 1 case in every 100,000 live births.

Sex- and age-related demographics

No difference in penetrance is reported between sexes.

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.

Prognosis

Cardiac disease and liver disease can significantly affect the life expectancy of patients with Alagille syndrome.

Patients with more significant cardiovascular anomalies (tetralogy of Fallot, pulmonary atresia [PA] with ventricular septal defect [VSD], atrial septal defect [ASD]/VSD, patent ductus arteriosus [PDA]) eventually require cardiac surgery. The 20-year predicted survival rate via Kaplan-Meier plots for individuals with significant intracardiac lesions is 40%; for those individuals without significant intracardiac lesions, the survival rate is 80%.

Morbidity/mortality

Major contributors to morbidity arise from bile duct paucity or cholestatic liver disease, underlying cardiac disease, CNS vasculopathy, Moyamoya disease, and renal disease.

Complications

Hepatic complications arise from cholestasis and cirrhosis. Infants may present with neonatal jaundice. Jaundice resolves by age 2 years or cholestasis persists. Unrecognized deficiencies of fat-soluble vitamins (A, D, E, K) can contribute to morbidity (eg, osteopenia, hemolytic anemia) and mortality (eg, intracranial hemorrhage, aberrant intracerebral vessels secondary to abnormal notch or JAG1 expression) from bleeding events. Severe intractable pruritus occurs in many children with Alagille syndrome, prompting consideration for liver transplantation. Several patients have developed hepatocellular carcinoma in early adulthood.

Major contributors to morbidity arise from bile duct paucity or cholestatic liver disease, underlying cardiac disease, and renal disease.

Structural cardiac disease and hyperlipidemia or atherosclerosis contribute to morbidity and mortality of Alagille syndrome. Cardiac murmurs are noted in fewer than 95% of patients. Structural anomalies associated with Alagille syndrome range from mild peripheral pulmonic stenosis to severe tetralogy of Fallot. Aneurysms and stenotic lesions have been described within the arterial system (eg, carotids, aorta, renal), as has the development of changes similar to Moyamoya disease. Hyperlipidemia commonly is manifested as xanthomas. Patients have high levels of plasma cholesterol, low-density lipoprotein (LDL), and apoprotein B, predisposing to the development of atherosclerosis.

Structural renal disease as well as glomerulosclerosis and nephrosclerosis have been described in patients with Alagille syndrome. Renal anomalies include renal artery stenosis, ectopic kidney, single kidney, and ureteral duplications. The development of glomerulosclerosis in patients with Alagille syndrome has been attributed to hypercholesterolemia and lecithin cholesterol acyltransferase (LCAT) deficiency, as well as stimulation of excessive production of extracellular matrix. One patient has been reported to require renal transplantation.

Clinical Presentation

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Media Gallery

Typical facial features of Alagille syndrome. Note broad forehead, deep-set eyes and pointed chin. Courtesy of University of Washington, Seattle (Pagon RA, Adam MP, Ardinger HH, et al, Eds. Seattle (WA): University of Washington, Seattle; 1993-2014. Available at: www.ncbi.nlm.nih.gov/books/NBK1116/).

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