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Alagille Syndrome

Alagille Syndrome

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Published by: arambakkam on Aug 05, 2009
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02/06/2013

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Alagille Syndrome
Author: Ann Scheimann, MD, MBA,
Assistant Professor, Department of Pediatrics,Section of Nutrition and Gastroenterology, Baylor College of Medicine and JohnsHopkins Medical InstitutionContributor Information and DisclosuresUpdated: Jun 18, 2008
Overview
Introduction
Background
Alagille syndrome (AS) is an autosomal dominant disorder (OMIM 118450) associated withabnormalities of the liver, heart, skeleton, eye, and kidneys and a characteristic facial appearance.
1
 In1973, Watson and Miller reported 9 cases of neonatal liver disease with familialpulmonary valvular stenosis.
2
Then in 1975, Alagille et al described several patients with hypoplasia of the hepatic ductswith associated features.
3
 
Pathophysiology
Alagille syndrome is an autosomal dominant disorder with variable expression. Associatedabnormalities include those of the liver, heart, eye, skeleton, and kidneys and characteristic facialfeatures. Mild-to-moderate mental retardation also may be present. The syndrome has recently beenmapped 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 completedeletion 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, underlyingcardiac 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, areoften diagnosed after an index case.
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 evaluationfor right-sided heart disease. Some individuals are diagnosed by careful examination after an indexcase is identified in the family.
Nutrition and growth
o
Children often present with poor linear growth.
o
Altered longitudinal growth is attributed to wasting or inadequate intake, and anelement of growth hormone resistance may also be present.
6
Studies to assess theimpact of higher doses of growth hormone on linear growth in patients with Alagillesyndrome are currently underway.
Head and neck
o
Commonly associated facial features include broadened forehead, pointed chin, andelongated nose with bulbous tip.
o
Characteristic facial features may not be obvious during infancy but may becomemore apparent as the child ages.
Ophthalmologic
o
Ocular abnormalities are common.
7
The most frequent ophthalmologic finding is aposterior embryotoxon, which was observed in more than 75% of patients in onelarge series conducted by Emerick et al.
8
 
 
o
Some of these patients may also have the Axenfeld anomaly (ie, iris attachment toDescemet membrane).
o
Other findings reported include retinitis pigmentosa, pupillary abnormalities, andanomalies of the optic disc.
Cardiovascular 
o
Nearly all patients have cardiac murmurs.
o
The most common cardiac lesions are stenoses within the pulmonary tree (peripheralpulmonic stenosis) with or without other structural lesions.
o
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 Alagillesyndrome at increased mortality risk.
Hepatic
o
Hepatic disease is a key feature of Alagille syndrome.
o
Most infants present with cholestatic jaundice.
o
Hepatosplenomegaly is common.
o
Elevations in serum bile acids often result in severe pruritus and xanthomas(hypercholesterolemia).
o
Fat-soluble vitamin deficiencies, including coagulopathies and rickets, are frequent.
Skeletal
o
Abnormalities of the vertebrae, ribs, and hands are frequently associated with Alagillesyndrome.
o
Butterfly hemivertebrae were found in one half of the patients analyzed by Emerick etal in a large series of patients with Alagille syndrome.
8
o
Other isolated anomalies include rib anomalies and shortening of the radius, ulna,and phalanges.
Neurologic
o
Mild developmental delay and mental retardation are reported in some children withAlagille syndrome.
o
If noted during the physical examination, diminished deep tendon reflexes shoulddirect the clinician to exclude vitamin E deficiency.
Renal: Occult renal artery stenosis, lipoid nephrosis, or glomerulosclerosis may present withsigns and symptoms of chronichypertension. 
Vascular: Vascular lesions have been recently described in 6% of the patients with confirmedAlagille syndrome who were followed by Kamath et al.
9
These lesions included basilar artery

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