Alagille Syndrome Clinical Care Program

Diagnosis and Evaluation of Alagille Syndrome


When Alagille syndrome was initially described, a diagnosis required that a person have bile duct paucity in addition to at least three of five major criteria:

Due to the successful identification of Jagged1 as the gene that causes Alagille syndrome, the diagnostic criteria have been modified. In recent years, it has been recognized that a diagnosis can be made in a person who does not have all of the clinical criteria of Alagille syndrome but does have a mutation in Jagged1. For example, a less severely affected family member who would not meet clinical criteria for AGS but who has the same Jagged1 mutation as a severely affected family member is considered to have AGS.

In the research laboratory at CHOP it is currently possible to identify a mutation in more than 90% of individuals that meet clinical criteria for AGS. A minority (<1%) of patients with Alagille syndrome have a mutation in another gene called Notch2. Mutation testing for this gene is currently only done on a research basis.


Because the manifestations and severity of Alagille syndrome can vary widely, it can often be difficult to diagnose. If your doctor suspects that your child has AGS then he or she may order a number of tests and do certain procedures to rule out other diseases and to help make a diagnosis.

Liver Function/Gastroenterology (GI)

Most individuals with Alagille syndrome have liver disease, though this may vary in its severity and can also change over time. Children usually develop jaundice in infancy and this is the most common time to undergo evaluation by a gastroenterologist.

An initial evaluation for liver disease will involve a physical examination at which the gastroenterologist will be particularly interested in assessing if the liver and/or spleen are enlarged. Liver function can be assessed by blood tests called liver function tests. These are a group of tests that include ALT, AST, GGT, albumin, bilirubin, conjugated bilirubin and PT/PTT.

If appropriate, further tests may be necessary. These may include an ultrasound of the abdomen, which can help to rule out other causes of jaundice and can assess the degree of enlargement of the liver and spleen. Sometimes a liver biopsy is helpful to make the diagnosis of Alagille syndrome, though this is not mandatory to make the diagnosis. This test is usually performed under conscious sedation and requires a small core of liver tissue being taken with a needle through the skin.

Pancreatic Function Tests: 72-hour Stool Collection

Doctors can indirectly assess pancreatic function with a 72-hour stool collection, in combination with a three-day dietary record, to determine how much fat a child is absorbing from the food he or she is eating. Because this collection is usually done at home, you will be given the supplies and instructions you need. All stools are collected in pre-weighed containers for 72 hours and frozen. Everything your child eats during these three days must be weighed and recorded. The laboratory then determines the amount of fat absorbed  (coefficient of fat absorption). Unfortunately, this test cannot distinguish between fat malabsorption due to liver disease and fat malabsorption due to pancreatic diseases.


Your child may also see a cardiologist (a physician who specializes in caring for hearts) who can rule out any mild heart problems.

The cardiologist will perform a complete physical examination and will most likely perform an ECG and echocardiogram. An ECG measures the heart rhythm. The echocardiogram is an ultrasound of the heart and will define the exact structure and function of the heart. Depending upon the results of the examination and these studies, the cardiologist may decide to order other tests or to arrange follow up visits in the future.

Ophthalmologic (Eye)

Many children with Alagille syndrome have an unusual abnormality of the eyes. Posterior embryotoxon, an extra, circular line on the surface of the eye, is the most common eye finding. This requires a specialized eye examination to detect and does not lead to any disturbances in vision. Pigmentary changes of the retina (thin layer of photoreceptors lining the inside wall of the eye) are present in some children with AGS. An ophthalmologist can examine your child's eyes to look for posterior embryotoxon and other eye abnormalities.

You can get more information by visiting the Division of Ophthalmology Web site.


X-rays of the spine can help detect "butterfly" vertebrae, the most common skeletal defect associated with Alagille syndrome. A clefting abnormality gives the vertebrae a "flying butterfly" appearance on X-rays. Generally, butterfly vertebrae do not cause any symptoms, but they do help with making a diagnosis.

Genetics Evaluation and Testing

If your child's physician suspects he or she has Alagille syndrome, your child should see a geneticist (a physician trained in genetics) and a genetic counselor. Most geneticists are trained in dysmorphology, or the study of how the face and body are formed. A geneticist will be able to evaluate your child for the facial features characteristic of Alagille syndrome.

Together, the geneticist and genetic counselor will review the results of the other diagnostic studies (such as eye exam, spine X-rays, etc.), as well as your family history. They will provide you with information about the genetics and inheritance pattern of Alagille syndrome. Based on the information gathered from your family history and genetic testing results, they can also address questions about the chance that future children in your family could be affected with Alagille syndrome.

Reviewed by: Bimita M. Kamath, MD
Date: January 2009


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