Alagille Syndrome

What are the other Names for this Condition? (Also known as/Synonyms)

• AHD (Arteriohepatic Dysplasia)
• Arteriohepatic Dysplasia (AHD)
• Cardiovertebral Syndrome

What is Alagille Syndrome? (Definition/Background Information)

• Alagille Syndrome is a genetic condition that affects the heart, liver, and several other important organs of the body. It is a multisystem disorder that affects many body organs. The disorder is seen among neonates with equal incidence between males and females
• In Alagille Syndrome, there is malformation of the bile ducts within the liver; these ducts are either narrowed, abnormally formed, or reduced in number
• These small ducts within the liver are responsible for transporting bile from the cells in the liver to the gallbladder that eventually makes its way into the small intestine
• The bile within the liver is important for two reasons - to remove harmful toxins and wastes out of the body and to help in the digestion of fatty material
• Unfortunately, because there is minimal availability of bile ducts in Alagille Syndrome, it causes an obstruction in the flow of bile, leading to a back-up of all the material that is not transported out of the liver. This eventually leads to liver damage and scarring
• Currently there is no treatment available for Alagille Syndrome. It has a poor prognosis, as there are currently no known effective treatment options to manage this genetic condition. It cannot be prevented too, since the condition is inherited

Who gets Alagille Syndrome? (Age and Sex Distribution)

• Alagille Syndrome is a rare inherited disorder seen in newborn children. Its incidence rate is 1 in 70,000 births. However, the condition  does not manifest until late infancy or early childhood
• Both male and female babies are equally prone to the disorder
• No specific research exists that indicates that the condition is more predominant among any particular racial or ethnic group

What are the Risk Factors for Alagille Syndrome? (Predisposing Factors)

• Alagille Syndrome is an inherited genetic condition. The affected individuals demonstrate significant family history, which is a risk factor for this condition to develop.

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases ones chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Alagille Syndrome? (Etiology)

• Alagille Syndrome is inherited as an autosomal dominant condition. The affected children have a 50% chance of inheriting this abnormal gene, either from the father or mother
• This abnormal gene that is affected in over 90% of the cases is the JAG1 gene, whose normal function is to determine the cell cycle. Sometimes, mutations may occur in another gene too, called the NOTCH2 gene
• Though Alagille Syndrome is an inherited condition, there are many cases where the disease occurred due to a new and sporadic change in the gene (genetic mutation). This is seen to occur in almost 50% of the cases, when there is no associated family history of the disorder

Autosomal dominant: Autosomal dominant conditions are traits or disorders that are present when only one copy of the mutation is inherited on a non-sex chromosome. In these types of conditions, the individual has one normal copy and one mutant copy of the gene. The abnormal gene dominates, masking the effects of the correctly function gene. If an individual has an autosomal dominant condition, the chance of passing the abnormal gene on to their offspring is 50%. Children, who do not inherit the abnormal gene, will not develop the condition or pass it on to their offspring.

What are the Signs and Symptoms of Alagille Syndrome?

The signs and symptoms of Alagille Syndrome can vary from one individual to another. In fact, even within families it can present differently.

The affected individuals may be observed to have:

• Jaundice: Yellowing of skin and whites of eyes
• Severe itching along the eyes and skin
• Xanthomas; cholesterol deposits on the skin
• Enlargement of liver and spleen
• Poor physical growth; big forehead, deep set eyes, straight nose, and small pointed chin
• Butterfly vertebra - failure of fusion of two halves of the vertebrae
• Shortened forearm and finger bones
• High blood pressure due to narrowing of the renal artery
• A type of heart murmur
• Narrowing of pulmonary (lung) arteries causing increased pressure on the right side of the heart
• Teratology of Fallot: A common heart defect observed in children affected by Alagille Syndrome and characterized by bluish discoloration of skin, shortness of breath on exertion, and failure to grow
• Poor-to-absent reflexes of the deep tendon
• Slow mental development; mental retardation
• Poor performance at school

How is Alagille Syndrome Diagnosed?

A diagnosis of Alagille Syndrome may involve:

• Physical examination with medical history evaluation: Alagille Syndrome is suspected when there is a family history of the condition and when the patient has certain symptoms of the heart, bone, eye, and face, along with bile duct flow disorder
• If there is a positive family history of the condition, the infant needs to be examined at about 6 months of age to exclude the possibility of Alagille Syndrome
• A blood test may be performed to evaluate complete blood count, along with a liver function test. Tests to evaluate the clotting status of the body, such as a PT and PTT test, may also be ordered
• A liver biopsy to assess the severity of the bile duct in the liver may be performed. The biopsy is sent to the laboratory for pathological examination. The pathologist examines the biopsy under a microscope for a definitive diagnosis
• An ultrasound scan of the organs, including the liver, lung, spleen, gallbladder, and intestine, may be conducted to examine which organs are affected (and to the extent they are affected)
• Nuclear scan (radiology procedure): To assess the flow of bile within the liver
• In some cases, a minor surgery may be performed to examine the extent of liver and bile duct damage

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Alagille Syndrome?

The complications with Alagille Syndrome may include:

• Liver damage with scarring of the liver
• It can also damage the kidneys, heart, spine, and eyes
• Narrowing of the renal artery causing high blood pressure
• Narrowing of the pulmonary (lung) arteries causing increased pressure on the right side of the heart

A very severe complication associated with Alagille Syndrome is bleeding within the brain leading to death. Even though it is a very rare complication, it can happen spontaneously.

How is Alagille Syndrome Treated?

Currently, there is no treatment available for Alagille Syndrome. The goal, in most cases, is to minimize the underlying symptoms and improve the heart condition. The treatment focuses on trying to reduce the effects caused by damage of the liver, kidney, and spleen.

• Vitamins and nutrients are given to individuals who are poorly nourished. In fact, because the body is not capable of digesting fat, the fat-soluble vitamins, such as A, D, E, and K, are given to help these individuals
• Some affected children may be able to take formulated drinks that are composed of smaller forms of fat, as tolerance level is better for fats in small form
• Based on the severity, some may require a nasogastric tube (tube placed from the nose to the stomach) in order to aid individuals consume some amount of calories and keep them better nourished
• Antihistamines and cholestyramine are given to help pruritus (sensation to itch)
• Individuals with severe forms of the disease and with great damage to the liver will require an immediate liver transplant

Though, there is no specific treatment available for Alagille Syndrome, suitable management measures are taken to keep the individual as comfortable as possible and to manage the health issues that are generally seen with this disorder.

How can Alagille Syndrome be Prevented?

• Currently, there are no specific methods or guidelines to prevent Alagille Syndrome, since it is a genetic condition
• Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy) may help in understanding the risks better during pregnancy
• If there is a family history of the condition, then genetic counseling will help assess risks before planning for a child
• Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders

What is the Prognosis of Alagille Syndrome? (Outcomes/Resolutions)

Alagille Syndrome has a poor prognosis, as there are currently no known effective treatment options available to manage this genetic condition.

Additional and Relevant Useful Information for Alagille Syndrome:

The disorder is also known as Hepatofacioneurocardiovertebral Syndrome (due to Alagille Syndrome), since it affects multiple organs in the body.