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Alagille Syndrome

About Alagille Syndrome (AS)

Alagille syndrome is a genetic disorder associated with liver, heart, kidney, skeletal, and eye abnormalities as well as a set of characteristic facial features. Facial features associated with Alagille syndrome include a broad, prominent forehead, deep-set eyes, and a small, pointed chin. Also, X-rays often reveal that individuals with Alagille syndrome have butterfly-shaped vertebrae in the spinal column. Generally, Alagille syndrome becomes evident in infancy or early childhood.

Why it is Problematic

In individuals with Alagille syndrome, liver damage is caused by abnormalities in the bile ducts that carry bile, a substance that helps to digest fats, from the liver to the gallbladder and small intestine. Bile ducts in individuals with Alagille syndrome are fewer in number, narrower than normal and malformed. As a result, bile builds up in the liver, causing scarring that prevents the liver from eliminating toxins from the blood.

Alagille syndrome is also associated with heart problems. Blood flow from the heart to the lungs (pulmonicstenosis) may occur in the lower chambers of the heart (ventricular septal defect).

Causes and Risk Factors

A genetic mutation in the JAG1 gene is responsible for about 90% of all cases of Alagille syndrome. Small deletions of genetic material on chromosome 20, including the JAG1 gene, represent approximately 7% of all reported cases. A very small number of people have mutations on the NOTCH2 gene.

About 30-50% of those with Alagille syndrome inherit the condition from one affected parent. Others are affected by new mutations in the gene or new deletions of genetic material on Chromosome 20 prior to birth. This process occurs randomly during reproductive cell formation in early fetal development and can be present in those with no family history of Alagille syndrome.

Symptoms

Symptoms, though most common in infants, can also occur in children and adults. The most noticeable symptoms reflect those of liver disease and poor bile drainage. These symptoms include:

Jaundice (the yellowing of the skin and whites of the eyes)
Itching (pruritus), typically occurring after 3 months of age, and potentially severe
Malabsorption and growth problems
Diarrhea
Xanthomas (harmless yellow bumps on the skin caused by fatty deposits,which are in turn caused by abnormally high cholesterol in the blood,and commonly found around the eyes, abdomen, knees, elbows and hands).

Some symptoms are unique to Alagille syndrome:

Heart murmuristhe most common sign of AS other than those of liver disease.
Facial characteristicsmay exist, such as deep-set eyes, a straight nose, a wide forehead, and a small pointed chin; inadulthood, the chin becomes more prominent.
The skeletonappears abnormal on x-ray; thevertebraeresemble a butterfly shape.
The blood vessels of the headand neck (carotid arteries)may have abnormalities. This canlead to stroke or internal bleeding. Should someone with Alagille syndrome suffer anaccident or injury to the head, it is imperative that he or she receive prompt medical attention. Alagille syndrome can also cause narrowing or expanding of other blood vessels within the body.
The kidneys may have impaired function or cysts, or they may be smaller than average.
The spleen may be enlarged, creating the potential for portal hypertension or other serious complications associated with liver disease.

Diagnosis

Alagille syndrome is difficult to diagnose, both because the condition is rare and because there are many potential symptoms.

As a rule, three of the following symptoms must be present for an AS diagnosis:

Liver symptoms
Heart murmur
Posterior embryotoxon (white ring around the iris)
Skeletal abnormalities
Characteristic facial features

If Alagille syndrome is suspected, genetic bloods test are performed to look for mutations on the JAG1 or NOTCH2 genes.

Treatment and Prevention

Treatment for Alagilles syndrome focuses on specific symptoms. These treatments include:

Prescribing of bile flow medications to increase the amount of bile flowing and to treat xanathomas related to abnormal, excessive cholesterol build-up through bile obstruction. Ursodiol is the only drug approved by the FDA to increase bile flow.
Attempts to eliminate malabsorption through a well-balanced, high-calorie diet. Hydration is also very important, and the patient must drink plenty of water each day. If the patient is unable to eat, a feeding (gastronomy) tube may be used to ensure adequate nourishment.
Prescribing of medication, in some cases, to better manage itching (pruritis). Pruritis may improve once bile flow has improved.

In extreme cases a procedure called partial external biliary diversion (PEBD) may be performed. This procedure entails surgically connecting one end of the small intestine to the gallbladder and the other end to the abdominal opening, called the stoma. This allows bile to leave the body. It is collected in an external bag.

In some individuals, Alagille syndrome may lead to liver failure and require a liver transplant.

Incidence

Alagille syndrome is a rare condition affecting about 1 in 70,000 infants.

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