Alagille syndrome

Alagille syndrome is a genetic disorder that can affect the liver, heart, and other systems of the body.

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), itching, and deposits of cholesterol in the skin (xanthomas). A liver biopsy may indicate too few bile ducts (bile duct paucity). These ducts carry bile (which helps to digest fats) from the liver to the gallbladder and small intestine.

Heart problems associated with Alagille syndrome may include impaired blood flow from the heart into the lungs for oxygenation (pulmonic stenosis). This defect may be combined with a hole between the two lower chambers of the heart (ventricular septal defect) and other problems in a condition called tetralogy of Fallot.

Facial features characteristic of Alagille syndrome include a broad, prominent forehead, deep-set eyes, and a small pointed chin. The disorder may also affect the kidneys and central nervous system, and cause an unusual butterfly shape of the bones of the spinal column 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, however, can vary within the same family, with symptoms ranging from so mild as to go unnoticed to severe heart and/or liver disease requiring transplantation.

Some people with Alagille syndrome may have only isolated signs of the disorder, such as characteristic facial features or heart defects. These individuals do not have liver disease or other features typical of the disorder.

The estimated prevalence of Alagille syndrome is 1 in every 70,000 people. This figure is based on diagnoses of liver disease in infancy, and may be an underestimation due to the varying severity and symptoms of the disorder. The prevalence of this disorder could be as high as 1 in 20,000 people if the frequency of gene mutations that cause Alagille syndrome is considered.

Mutations in the JAG1 and NOTCH2 genes cause Alagille syndrome.

The JAG1 and NOTCH2 genes provide instructions for making proteins that fit together to trigger signaling between neighboring cells during embryonic development. This signaling influences how the cells are used to build body structures in the developing embryo. Mutations in either the JAG1 gene or NOTCH2 gene probably disrupt the signaling pathway. As a result, errors may occur during development, especially affecting the heart, bile ducts in the liver, spinal column, and certain facial features.

Narrowed and malformed bile ducts in the liver produce many of the health problems associated with Alagille syndrome. In this disorder, bile builds up in the liver and causes scarring that prevents the liver from working properly to eliminate wastes from the bloodstream.

This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder.

In approximately 30 percent to 50 percent of cases, an affected person inherits the mutation from one affected parent. Other cases result from new mutations in the gene. These cases occur in people with no history of the disorder in their family.