DEFINITION
The disease definition according to a specific consensus conference or to The Diseases Database based on the Unified Medical Language System (NLM)
A multisystem disorder that is characterized by aplasia of intrahepatic bile ducts (bile ducts, intrahepatic), and malformations in the cardiovascular system, the eyes, the vertebral column, and the facies. Major clinical features include jaundice, and congenital heart disease with peripheral pulmunary stenosis.
Alagille syndrome may result from heterogeneous gene mutations, including mutations in JAG1 on CHROMOSOME 20 (Type 1) and NOTCH2 on CHROMOSOME 1 (Type 2).
Pubmed: Alagille Syndrome - Genereview
EPIDEMIOLOGY
The prevalence of ALGS was originally estimated at 1:70,000 live births; however, this is most likely an underestimate. Based on the work by Kamath et al, the authors estimate that the incidence of ALGS is 1:30,000-1:50,000 live births, but due to the variable phenotype, it remains underdiagnosed. The prevalence across populations appears to be stable.
Pubmed: Kamath et all 2003
SYMPTOMS
Alagille syndrome (ALGS) is a multisystem disorder. Studies have demonstrated a wide spectrum of clinical variability ranging from life-threatening liver or cardiac disease to only subclinical manifestations (i.e., butterfly vertebrae, posterior embryotoxon, or characteristic facial features).
Hepatic manifestations. Although some individuals with JAG1 mutations have no detectable hepatic manifestations, in most affected persons liver disease presents within the first three months of life and ranges from jaundice, mild cholestasis, and pruritis to progressive liver failure.
In approximately 15% of affected individuals, the liver disease progresses to cirrhosis and liver failure, necessitating liver transplantation. Currently, it is not possible to predict which infants will progress to end-stage liver disease.
Cardiac manifestations. Cardiac findings ranging from benign heart murmurs to significant structural defects occur in 90%-97% of individuals with ALGS. The pulmonary vasculature (pulmonary valve, pulmonary artery, and its branches) is most commonly involved. Pulmonic stenosis (peripheral and branch) is the most common cardiac finding (67%) [Emerick et al 1999]. The most common complex cardiac defect is tetralogy of Fallot, seen in 7%-16% of individuals [Emerick et al 1999]. Other cardiac malformations include (in order of decreasing frequency) ventricular septal defect, atrial septal defect, aortic stenosis, and coarctation of the aorta.
Ophthalmologic manifestations. The most common ophthalmologic finding in individuals with ALGS is posterior embryotoxon..
Other defects of the anterior chamber seen in ALGS include Axenfeld anomaly and Rieger anomaly.
Skeletal manifestations. The most common radiographic finding is butterfly vertebrae, a clefting abnormality of the vertebral bodies that occurs most commonly in the thoracic vertebrae. . Butterfly vertebrae are usually asymptomatic. Other skeletal manifestations in individuals with ALGS have been reported less frequently [Zanotti S, Canalis E. Notch and the skeleton. Mol Cell Biol. 2012;30:886–96].
Facial features. The constellation of facial features observed in children with ALGS includes a prominent forehead, deep-set eyes with moderate hypertelorism, pointed chin, and saddle or straight nose with a bulbous tip. These features give the face the appearance of an inverted triangle. The typical facial features are almost universally present in Alagille syndrome.
Altough the facial phenotype in ALGS is specific to hthe syndrome and is often a powerful diagnosis.
Pubmed - Alagille Symptoms
DIAGNOSIS
Clinical Diagnosis
The clinical diagnostic criteria for Alagille syndrome include the following:
The histologic finding of bile duct paucity (an increased portal tract-to-bile duct ratio) on liver biopsy and three of the following five major clinical features (in addition to bile duct paucity):
-Cholestasis
-Cardiac defect (most commonly stenosis of the peripheral pulmonary artery and its branches)
-Skeletal abnormalities (most commonly butterfly vertebrae identified in AP chest radiographs)
-Ophthalmologic abnormalities (most commonly posterior embryotoxon)
-Characteristic facial features
In addition, abnormalities of the kidney, neurovasculature, and pancreas are important manifestations of Alagille syndrome [Kamath et al 2012b, Turnpenny & Ellard 2012].
Bile duct paucity is not present in infancy in many individuals ultimately shown to have ALGS. In the newborn, a normal ratio of portal tracts to bile ducts, bile duct proliferation, or a picture suggestive of neonatal hepatitis may be observed. Overall, bile duct paucity is present in about 90% of individuals.
Anyway the diagnosis of Alagille syndrome may be difficult because of the highly variable expressivity of the clinical manifestations [Goldman & Pranikoff 2011, Guegan et al 2012].
To establish the extent of disease and needs in an individual diagnosed with Alagille syndrome, the following evaluations are recommended:
Evaluation by a gastroenterologist, including a full set of liver function tests, clotting studies and if necessary, serum bile acids, fat-soluble vitamin levels, a hepatic ultrasound, a technitium-99m-DISIDA scintiscan, and liver biopsy
A full cardiac evaluation, including echocardiogram
AP and lateral chest radiographs to evaluate for the presence of butterfly vertebrae
An ophthalmologic examination to identify anterior chamber involvement
Renal function testing and renal ultrasound examination (especially in the newborn period)
Screening developmental evaluation, with more detailed evaluation if significant delays are identified
Measurement of growth parameters and plotting on age-appropriate growth charts
Medical genetics consultation
Molecular Genetic Testing
Genes
Mutations in JAG1 are known to cause about 94%-96% of cases of ALGS.
Mutations in NOTCH2 are known to cause ALGS in 1%-2% of individuals.
Pubmed: Alagille Diagnosis
PATHOGENESIS
JAG1
The full role of the JAG1 protein in the devolepement of new ducts in infancy is not yet clear.
Jagged-1 is a cell surface protein that functions as a ligand for the neurogenic locus notch homolog protein 2 (Notch) transmembrane receptors, key signaling molecules found on the surface of a variety of cells. It functions in many cell types throughout development to regulate cell fate decisions.
More than 226 mutations have been identified in individuals with Alagille syndrome (ALGS) (~70% of those tested). Mutation types have included: deletion of the entire JAG1 gene (4%), protein-truncating mutations (frameshift and nonsense) (69%), splicing mutations (16%), and missense mutations (11%).
Haploinsufficiency of Jagged-1 is likely the pathogenic mechanism in the majority of cases of ALGS, as most mutations result in or predict a severely truncated protein product, lacking the transmembrane region necessary for the protein product to embed in the cell membrane and participate in signaling.
NOTCH2
Neurogenic locus notch homolog protein 2 (Notch 2) encodes a member of the Notch family of transmembrane receptors. Notch family members play a role in a variety of developmental processes by controlling cell fate decisions. This protein is cleaved in the trans-Golgi network, and presented on the cell surface as a heterodimer. The protein functions as a receptor for membrane-bound ligands and may play a role in vascular, renal, and hepatic development.
Ten different mutations have been identified one splice site alteration, one frameshift mutation, one nonsense mutation, and seven missense mutations.
THERAPY
A multidisciplinary approach to the management of individuals with ALGS is often beneficial because of the multisystem involvement. Evaluation by specialists in medical genetics, gastroenterology, nephrology, nutrition, cardiology, ophthalmology, liver transplantation, and child development may be indicated, depending on the age and specific difficulties of the individual [Kamath et al 2010a].
Pruritus is considered the most severe of any pediatric liver disease. Pruritis and xanthomas have been successfully treated with choloretic agents (ursodeoxycholic acid) and other medications (cholestyramine, rifampin, naltrexone).
Liver transplantation for end-stage liver disease has an 80.4% five-year survival rate. The lower success rate of liver transplantation in ALGS is probably most influenced by the severity of any coexisting cardiac disease, renal disease, or vascular involvement [Kamath BM, Yin W, Miller H, Anand R, Rand EB, Alonso E, Bucuvalas J. Studies of Pediatric Liver Transplantation. Outcomes of liver transplantation for patients with Alagille syndrome: the studies of pediatric liver transplantation experience. Liver Transpl. 2012c;18:940–8].
Cardiac involvement is treated in a standard manner.
Renal anomalies are treated in a standard manner.
Vascular accidents should be treated in a standard manner.
Head injuries and neurologic symptoms should be evaluated aggressively.
Ophthalmologic abnormalities rarely need intervention.
Vertebral anomalies are rarely symptomatic.
Optimization of nutrition to maximize growth and development
Close monitoring of plasma concentration of fat-soluble vitamins, nutritional optimization, and vitamin replacement therapy to maximize growth potential and prevent some of the developmental delay documented in early studies
For those with splenomegaly or with known chronic liver disease, use of a spleen guard during activities
Contact sports shoul be avoided
Individuals with liver disease should avoid alcohol consumption.
