Alagille syndrome

Medical quality assurance by Dr. Albrecht Nonnenmacher, MD at December 29, 2016
StartDiseasesAlagille syndrome

Alagille syndrome is a rare genetic disorder that primarily affects the liver but can also affect other parts of the body, including the heart. The condition typically manifests during infancy or early childhood. The severity of symptoms can vary widely from person to person.

Contents

Definition & Facts

Alagille syndrome is believed to affect approximately 1:30,000 to 1:70,000 infants; however, the actual incidence of the condition may be higher since some individuals have such mild symptoms that they go undiagnosed. The condition was first identified in 1969 by a French hepatologist named Daniel Alagille who described a group of children with a form of liver disease, heart problems, and unique facial features.

Individuals with the condition have a reduced number of bile ducts in their liver. These small tubes are responsible for carrying bile from the liver to the gallbladder and small intestine. Bile helps remove wastes from the body and aids in the digestion of fats and fat-soluble vitamins. The lack of sufficient bile ducts allows bile to collect in the liver where it can cause damage.

Symptoms & Complaints

Alagille syndrome can cause a wide range of symptoms affecting numerous parts of the body. Liver damage can cause a yellowing of the skin and eyes (jaundice), dark urine, and gray stools, itchy skin, and fatty deposits causing yellow bumps on the skin.

Children with Alagille syndrome often have a prominent forehead, deep-set eyes, pointed chin, straight nose, and large ears. An X-ray of the spine may reveal vertebrae that resemble flying butterflies. Many patients with Alagille syndrome have an opaque ring in the cornea of the eye, but it normally does not affect vision.

Heart abnormalities, including heart murmurs, valve problems, and blood vessel problems are also common with Alagille syndrome. The condition can also result in kidney disease leading to a decrease in kidney function.

If left untreated, individuals with Alagille syndrome can experience chronic liver failure, portal hypertension caused by a backup of blood into the spleen, an inability to absorb nutrients from food, and growth problems. Several related disorders involving the liver, including extrahepatic biliary atresia in which the bile ducts are situated outside the liver and neonatal hepatitis, can produce symptoms similar to Alagille syndrome.

Causes

Alagille syndrome is the result of a genetic mutation. In most cases, the mutation involves the JAG1 gene located on chromosome 20 or the NOTC 2 gene located on chromosome 1. In 30 to 50 percent of cases, the mutation is inherited. In the remaining cases, the defect occurs spontaneously. In a small percentage of Alagille patients, the JAG1 gene is missing completely. This is normally associated with more severe symptoms.

The mutation that causes Alagille syndrome is autosomal dominant, which means that a child only has to inherit the mutation from one parent in order to have the condition. Each child of an individual with the condition has a 50 percent chance of inheriting the defective gene. Even members of the same family with the same genetic mutation can experience vastly different symptoms. Alagille syndrome appears to affect males and females in roughly equal numbers. 

Diagnosis & Tests

The diagnosis of Alagille syndrome is complicated by the fact that symptoms can vary widely. An individual will typically be diagnosed with Alagille syndrome if they exhibit three of following clinical criteria:

  • A decreased number of bile ducts
  • Skeletal abnormality
  • Distinctive facial features
  • Eye abnormality
  • Heart defect
  • Symptoms of liver disease

Laboratory tests such as blood tests, clinical urine tests, and stool tests may be used to evaluate liver, kidney, and pancreatic function. An abdominal ultrasound may be ordered to rule out other causes of jaundice and liver enlargement (hepatomegaly) and spleen enlargement (splenomegaly). A liver biopsy may be performed to remove a small portion of liver tissue to check for a lack of sufficient bile ducts.

Children with Alagille syndrome typically benefit from a referral to a cardiologist to rule out any heart problems. The cardiologist may perform an echocardiogram, which is a type of ultrasound, to evaluate the function and structure of the heart. An EKG may also be used to assess the heart rhythm. A specialized eye examination may be used to detect the presence of opaque rings on the cornea, which occurs in some patients with Alagille syndrome. An X-ray may help confirm the diagnosis by revealing butterfly-shaped vertebrae, which are common with the condition. 

Treatment & Therapy

Many patients with Alagille syndrome are able to manage their symptoms and lead full, productive lives with proper treatment. Current treatments are aimed at increasing bile flow from the liver, helping children with the condition achieve normal growth and development, and correcting nutritional deficiencies resulting from malabsorption.

Ursodeoxycholic acid may help improve bile flow. Antihistamines, colestyramine, rifampicin, and naltrexone may also be used to treat the itching and fatty skin deposits associated with Alagille syndrome.

Infant formulas with high amounts of medium-chain triglycerides and oral or injectable fat-soluble vitamins may be required to combat malabsorption and nutritional deficiencies. Approximately 10 to 30 percent of individuals with Alagille syndrome will eventually require a liver transplant because of severe liver damage. 

Prevention & Prophylaxis

There is no cure or way to prevent Alagille syndrome. Those with the condition should work with their healthcare provider or registered dietitian to help overcome the malabsorption that can lead to poor growth, delayed puberty, and developmental delays.

Children with Alagille syndrome are encouraged to eat high-calorie diets to compensate for the fat lost through the stool and to ensure that they receive enough calories to grow properly. Individuals with Alagille syndrome should be cautious about drinking alcohol, especially if liver function is known to be compromised.

People with a known or suspected personal or family history of Alagille syndrome may want to undergo genetic testing to check for the specific genetic mutation that causes the condition. Those considering genetic testing are encouraged to consult a genetic counselor before undergoing the test to get a better understanding of how the results will impact both them and their family members. Anyone with Alagille syndrome should have regular follow-ups with their health care team to limit the possibility of complications.