Alagille syndrome

December 31, 2014

Synonyms

Overview

Alagille syndrome is an inherited disorder in which a person has fewer than the normal number of small bile ducts inside the liver. It is a complex disorder that can affect other parts of the body including the heart, kidneys, blood vessels, eyes, face, and skeleton. Symptoms typically present in infancy or early childhood. The severity of the disorder varies among affected individuals, even within the same family. Symptoms range from so mild as to go unnoticed to severe enough to require heart and/or liver transplants.

One of the major features of Alagille syndrome is liver damage caused by abnormalities in the bile ducts. These ducts carry bile (which helps to digest fats) from the liver to the gallbladder and small intestine. In Alagille syndrome, the bile ducts may be narrow, malformed, and reduced in number (bile duct paucity). As a result, bile builds up in the liver and causes scarring that prevents the liver from working properly to eliminate wastes from the bloodstream. Signs and symptoms arising from liver damage in Alagille syndrome may include a yellowish tinge in the skin and the whites of the eyes (jaundice), itchy skin, and deposits of cholesterol in the skin (xanthomas).

Alagille syndrome is also associated with several heart problems, including impaired blood flow from the heart into the lungs (pulmonic stenosis). Pulmonic stenosis may occur along with a hole between the two lower chambers of the heart (ventricular septal defect) and other heart abnormalities. This combination of heart defects is called tetralogy of Fallot.

People with Alagille syndrome may have distinctive facial features including a broad, prominent forehead; deep-set eyes; and a small, pointed chin. The disorder may also affect the blood vessels within the brain and spinal cord (central nervous system) and the kidneys. Affected individuals may have an unusual butterfly shape of the bones of the spinal column (vertebrae) that can be seen in an x-ray.
Problems associated with Alagille syndrome generally become evident in infancy or early childhood. The severity of the disorder varies among affected individuals, even within the same family. Symptoms range from so mild as to go unnoticed to severe heart and/or liver disease requiring transplantation.

Some people with Alagille syndrome may have isolated signs of the disorder, such as a heart defect like tetralogy of Fallot, or a characteristic facial appearance. These individuals do not have liver disease or other features typical of the disorder.

Symptoms

Alagille syndrome is a complex multisystem disorder involving the liver, heart, eyes, face, and skeleton. Symptoms typically present in infancy or early childhood. The severity of the disorder varies among affected individuals, even within the same family. Symptoms range from so mild as to go unnoticed to severe enough to require heart and/or liver transplants.

One of the major features of Alagille syndrome is liver damage caused by abnormalities in the bile ducts. These ducts carry bile (which helps to digest fats) from the liver to the gallbladder and small intestine. In Alagille syndrome, the bile ducts may be narrow, malformed, and reduced in number. This results in a build-up of bile causing scarring that prevents the liver from working properly. This may lead to jaundice, itchy skin, and deposits of cholesterol in the skin (xanthomas).

Alagille syndrome is also associated with several heart problems, including impaired blood flow from the heart into the lungs (pulmonic stenosis). Other heart-related problems include a hole between the two lower chambers of the heart (ventricular septal defect) and a combination of heart defects called tetralogy of Fallot.

People with Alagille syndrome may also have distinctive facial features (including a broad, prominent forehead; deep-set eyes; and a small, pointed chin), problems with the blood vessels within the brain and spinal cord (central nervous system) and the kidneys, and an unusual butterfly shape of the bones of the spinal olumn (vertebrae).

Symptoms, including jaundice, pale, loose stools, and poor growth, typically develop in the first 2 years of life. Symptoms and symptom severity varies, even among people in the same family.

Biliary tract abnormality
Corneal dystrophy
Hepatomegaly
Ventricular septal defect

Causes

Alagille syndrome is caused by mutations in one of two genes – the JAG1 gene or the NOTCH2 gene. Mutations of the JAG1 gene have been identified in more than 88 percent of cases. Mutations in the NOTCH2 gene account for less than 1 percent of cases. These mutations are inherited as autosomal dominant traits. In some cases, the mutations occur randomly due to a spontaneous genetic change (i.e., new mutation).

Genetic disorders are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of a gene with a mutation is necessary for the appearance of the disorder. The gene with the mutation can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. If carried by a parent the risk of passing the gene with the mutation from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child.

Investigators have determined that the majority of cases of Alagille syndrome occur due to mutations of the JAG1 gene located on the short arm (9) of chromosome 20 (20p12). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated "p" and a long arm designated "q". Chromosomes are further sub-divided into many bands that are numbered. For example, "chromosome 20p12" refers to band 1, sub-band 2, on the short arm of chromosome 20. The numbered bands specify the location of the thousands of genes that are present on each chromosome.

In approximately 6-7 percent of Alagille syndrome cases, individuals have a complete deletion or loss of the JAG1 gene. These individuals may have a more severe form of Alagille syndrome depending on how large the deletion is and how many other genes on chromosome 20 are involved.

Investigators have determined that the NOTCH2 gene is located on the short arm of chromosome 1 (1p13-p11).

Diagnosis

A diagnosis of Alagille syndrome is made based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Because the symptoms of Alagille syndrome are highly variable, obtaining a diagnosis can be difficult. Surgical removal and microscopic study of liver tissue (liver biopsy) can reveal bile duct paucity. Although bile duct paucity is considered a key characteristic of Alagille syndrome, this finding is not always present in infants with the disorder.

A physician may suspect Alagille syndrome if an individual has three of the following five clinical finding in addition to bile duct paucity cholestasis; heart defect; skeletal abnormality; eye (ophthalmologic) abnormality; and/or distinctive facial features.

In addition to a liver biopsy, physicians may conduct other tests to aid in the diagnosis of Alagille syndrome. Such tests may include blood tests to determine liver function and detect fat-soluble vitamin deficiencies, an eye examination, x-rays of the spine to detect characteristic changes such as butterfly vertebrae, an abdominal ultrasound of the hepatobiliary tree (e.g., liver, pancreas, gall bladder and spleen) to detect abnormalities or rule out other conditions, and an examination of heart structure and function to detect potential heart abnormalities.

The diagnosis of Alagille syndrome can be confirmed in many cases by molecular genetic testing, which reveals the presence of a JAG1 or NOTCH2 mutation.

Prognosis

The outlook for people with Alagille syndrome depends on several factors, including the severity of liver damage and heart problems and the early correction of malabsorption. Predicting who will experience improved bile flow and who will progress to end-stage liver failure is difficult. Fifteen percent of people with Alagille syndrome will eventually require a liver transplant.

Research studies report that 75 percent of children diagnosed with Alagille syndrome live to at least 20 years of age. Because of improvements in liver and heart therapies, this survival rate is increasing. Many adults with Alagille syndrome who improve with treatment lead normal, productive lives. Deaths in people with Alagille syndrome are most often caused by liver failure, heart problems, and blood vessel abnormalities.

Treatment

Treatment is symptomatic and supportive and There is no known cure for Alagille's Syndrome. Most of the treatments available are aimed at improving the functioning of the heart, and reducing the effects of impaired liver function. In severe cases, liver transplant may be necessary.