Alagille syndrome

Overview

Alagille syndrome is a rare genetic disorder that can affect the liver and other parts of the body. Infants with Alagille syndrome often have fewer than normal bile ducts in the liver. Bile ducts may also be narrower than usual or malformed.

As a result, bile (a fluid that helps with digestion) builds up in the liver, causing damage and scarring, and can also enter the blood and skin. Digestion of fats and certain vitamins (A, D, E and K) is also reduced. In addition to liver problems, Alagille syndrome may affect the heart, blood vessels, bones, kidneys and facial structure.

The severity and symptoms of Alagille syndrome vary greatly from one person to another, even within the same family. Some patients have serious problems with the liver, heart, other organs and bones. Others have only mild symptoms that don't pose any health issues and may even go unnoticed. Whether or not they have symptoms, any person with Alagille syndrome can pass the disorder on to their child.

About 1 baby in 30,000 is born with Alagille syndrome, which occurs in both sexes equally. The disorder is caused by a genetic mutation (a permanent change in the DNA sequence) on either the JAG1 or NOTCH2 gene.

Alagille syndrome is an autosomal dominant disorder, which means that a person with one mutated copy of the gene will have the disorder. In about half of patients, this mutation is inherited from a parent. A child who has one parent with Alagille syndrome has a 50 percent chance of inheriting it. In the other patients, the mutation develops spontaneously.

Signs and symptoms

The first signs and symptoms of Alagille syndrome often appear in babies or young children. In some patients, liver problems are the first to arise. Symptoms may include:

• Jaundice (yellowing of the skin and white parts of the eyes)
• Hard bumps on the skin (caused by cholesterol deposits)
• Severe skin itchiness (pruritis)
• Loose bowel movements
• Pale-colored stools
• Dark or amber-colored urine
• Slow or delayed growth

Alagille syndrome can also cause problems with the heart and blood vessels, such as:

• Heart murmur (a whooshing sound detected in an exam that may or may not indicate a heart problem)
• Abnormalities in the heart valves and walls, such as pulmonic stenosis (a valve issue that reduces blood flow between the heart and lungs) or ventricular septal defect (a hole in the wall that separates the two lower chambers of the heart), that may require surgery
• Problems with blood vessels in the head, neck or other parts of the body

Other signs and symptoms of Alagille syndrome include:

• Kidney problems, such as cysts or reduced kidney function
• Skeletal abnormalities, including butterfly-shaped vertebrae (bones in the spinal column)
• Eye abnormalities, such as a white or gray ring on the cornea, the outermost layer of the eye
• A characteristic facial appearance (a broad forehead, deep-set eyes, and a small, pointed chin)

Diagnosis

Because Alagille syndrome is rare, and its signs and symptoms vary between patients, it can be difficult to diagnose. Your child's doctor will begin by conducting a physical exam and asking questions about both patient and family medical history.

The doctor may also order one or more of the following tests:

• Blood tests and urinalysis. These tests can detect problems with the liver and kidneys, as well as elevated levels of cholesterol and triglycerides.
• X-ray. A spinal X-ray may be used to check for the butterfly-shaped vertebrae characteristic of Alagille syndrome.
• Abdominal ultrasound. This test can reveal an enlarged or damaged liver, as well as help rule out other conditions.
• Echocardiogram. This ultrasound of the heart can detect the valve disorder known as pulmonic stenosis or other heart problems characteristic of Alagille syndrome.
• Slit-lamp exam. In this eye exam, a microscope and a thin beam of light are used to check for problems with the cornea.
• Liver biopsy. A provider uses a needle to remove a tiny tissue sample from the liver, which is then examined under a microscope.

The doctor also may refer your child to other specialists, such as a cardiologist or a nephrologist (kidney specialist), to help with the evaluation.

If a physical exam, medical history and other tests reveal multiple signs and symptoms of Alagille syndrome, your child's provider will order a genetic test to confirm the diagnosis. The test is done using a blood or saliva sample, which is analyzed in a specialized genetics lab. If the test shows a mutation in the JAG1 or NOTCH2 gene, a diagnosis of Alagille syndrome is confirmed.

Treatment

Treatment for Alagille syndrome involves addressing its symptoms and preventing complications, often with the combined help of several specialists. This may involve medication, dietary changes, surgery or other approaches.

Treatment for liver problems

For patients with liver problems, which often include itching, jaundice and poor growth, a top priority is to reduce the buildup of bile in the liver and throughout the body. Your child's doctor may start by prescribing an ileal bile acid transport (iBAT) inhibitor, a medication that blocks the reabsorption of bile from the intestine. This results in lowered bile levels in the liver and skin, which can relieve itching, minimize liver injury and improve growth.

For less severe cases, your child's doctor may prescribe medication that improves the flow of bile. Other medicines, including naltrexone, rifampin and antihistamines, can also help reduce itchiness.

A special diet and vitamin supplements may be prescribed to reduce the malnutrition and growth delay that can occur with Alagille syndrome. For babies with liver disease, a formula rich in medium chain triglycerides (MCTs) can improve the absorption of nutrients. Your child may be put on a high-calorie diet (sometimes delivered through a feeding tube) to help boost growth.

Even with medications and nutritional support, some children with Alagille syndrome have ongoing liver problems. Those with severe liver damage (cirrhosis) may need a liver transplant, which cures the liver disease caused by the condition.

Treatment for other concerns

Children with Alagille syndrome may have other health issues that require additional treatment, for example in the heart, the kidneys or the blood vessels in the brain. Specialists in each of these areas collaborate to monitor and treat each symptom.