Alagille syndrome

One of the symptoms of bile buildup is itchy skin. When the bile cannot get out of your liver and into your gall bladder and intestines as well as it should, it can start to get into your skin and build up there. This can be treated with medicine to help the bile flow out of the liver or medicines that decrease itching (antihistamines). You can also use lotions to help soothe the skin.

We don’t yet know why different people show different symptoms of Alagille syndrome, even if they have the same gene change or mutation. Likely, there are other genetic and environmental factors that cause a person to have more mild or more severe symptoms. We just don’t yet know what these factors are at this time.

First-degree relatives (parents, siblings, and children) should be tested for Alagille syndrome since the condition can cause very different symptoms in different people, and may not have been picked up in others until your diagnosis. If you have had genetic testing that found a JAG1 or NOTCH2 mutation, your relatives can be tested for that same mutation. If no mutation was found, other family members cannot be genetically tested. However, these relatives can be seen by doctors to look at their liver, heart, eyes, skeleton, and facial features to help determine if they have Alagille syndrome or not.

The Alagille Syndrome Foundation (www.alagille.org) makes it easy to connect with other people with Alagille syndrome. They have a 3-day get-together (a symposium) every three years that you can attend to learn more about Alagille syndrome and meet other people and families affected by the condition.

You can also connect to other people in your area with liver conditions through the American Liver Foundation (www.liverfoundation.org).

Usually, people with Alagille syndrome start having symptoms as babies or in early childhood. However, sometimes people have very mild symptoms of Alagille syndrome and they might not know they have it until much later in life.

While the liver, heart, eyes, face, and skeleton are most commonly affected by Alagille syndrome, there are some other symptoms that can be seen. People with Alagille syndrome can have problems with their kidneys and pancreas. They can also be shorter and might go through puberty later than other people their age. They may also have an increased risk of having developmental delays and an increased risk of having a stroke.

People with Alagille syndrome typically see many doctors who are experts in different body systems, including:

"Penetrance" refers to how often people with a gene change/mutation have the disorder associated with it. "Complete penetrance" means that all people with gene changes/mutations have the disorder. Alagille syndrome does not have complete penetrance. Currently, the penetrance of JAG1 mutations appears to be about 96%. This means that 96% of people with JAG1 mutations will have symptoms of Alagille syndrome. In other words, 4% of people with JAG1 mutations will have no symptoms of Alagille syndrome. NOTCH2 variants appear to have complete penetrance.

Alagille syndrome is a genetic condition that affects many parts of the body including the liver and heart. In most individuals with this condition, liver problems are the predominant feature of the disease. They may also have issues with their heart, skeleton (bones), eyes, and facial features that are similar to other people who have this condition. The symptoms of Alagille syndrome can be very different in different people, even if they are in the same family. The most common symptoms are problems with their liver-caused by abnormalities in the bile duct, differences in the structure of the heart, common facial features, and vertebrae (bones of the spine) shaped like butterflies. It is inherited in an autosomal dominant manner, meaning that having a change in one copy of a gene involved in Alagille syndrome is enough to cause the condition. The genes involved in Alagille syndrome are JAG1 and NOTCH2. Alagille syndrome can be inherited from a parent who has the syndrome or can be new in a child.

The main health problems in Alagille syndrome are liver and heart problems. People with Alagille syndrome can have severe liver disease due to bile backing up into the liver, causing it to scar and not work as well. You should be watching out for yellowing of the skin and eyes and itchy skin because these are symptoms of liver damage. People with Alagille syndrome can also be born with heart problems, especially problems in the vessels that carry blood from the heart to the lungs and differences in the structure of the heart. While these are usually found shortly after birth, mild heart problems might not appear until later in life. You should look out for shortness of breath, chest pain, fainting, and fast or slow heart beats.

The job of a gene is to make a protein. Normally, JAG1 makes a protein called Jagged-1 and NOTCH2 makes a protein called Notch 2. These proteins work in the cell to allow for communication between different cells as the baby develops before it is born. This communication is used to build the body properly. Changes in either of these genes causes the proteins to work less or not at all. This probably disrupts the communication between cells and might prevent the body from developing properly. The bile ducts, heart, spine bones, eyes, and face are the main parts of the body affected by the disruption in communication.

There are two genes known to be involved in Alagille syndrome. Changes/mutations in the gene JAG1 cause about 94-96% of Alagille syndrome. The type of changes in the gene can range from "spelling mistakes" to missing or added gene pieces. About 89% of Alagille syndrome is caused by spelling mistakes in JAG1. About 5-7% of Alagille syndrome is caused by big extra or missing pieces of JAG1. Spelling mistakes in the gene NOTCH2 cause about 1-2% of Alagille syndrome. The cause of the remaining 2-5% of Alagille syndrome is not yet known.

"Characteristic facial features" means that people with Alagille syndrome share some parts of their appearance. It does not mean that there is anything wrong with their faces or that they have a deformity or problem with their faces. Typically, people with Alagille syndrome will have a large forehead, eyes that sit deeper in their heads, a pointed chin, and a bigger tip of the nose. Several of these features may be seen in the general population, but may be more common in patients with Alagille Syndrome. Since these facial features are seen in most people with Alagille syndrome, doctors often use them to diagnose someone with the condition.

Everyone has spelling differences in their genes. That’s what makes us all different! A "variant" is a genetic spelling difference that has never been seen before or is not understood very well. If you have inherited a "variant" in JAG1 or NOTCH2, it means that there is a difference in how your JAG1 or NOTCH2 gene is spelled, but that we don’t yet know if this difference makes the gene work less or if it is just the way your JAG1 or NOTCH2 gene is normally spelled.
Since Alagille syndrome is inherited in an "autosomal dominant" manner, a change in one copy of your JAG1 or NOTCH2 gene is enough to cause the condition. If you have symptoms of Alagille syndrome and you have a variant in JAG1 or NOTCH2, it makes it more likely that the variant is a change that causes the gene to work less or not at all. If you have a variant in JAG1 or NOTCH2 and don’t have symptoms of Alagjlle syndrome, it makes it less likely (but not impossible) that the variant is causing the gene to work less or not at all.

The main symptoms of Alagille syndrome affect the liver, heart, eyes, face, and skeleton (bones). Liver damage is very common in Alagille syndrome. This damage happens because the bile ducts, the tubes that carry bile from the liver to the gall bladder and the small intestine, do not form properly. Bile helps us digest fats. The bile ducts might be formed differently or there might not be enough of them. This causes bile to back up in the liver and can damage it. Someone with liver damage can have yellow skin and eyes (known as jaundice) and itchy skin.
People with Alagille syndrome can also have heart problems. The most common heart problem is a difference in the blood flow from the heart to the lungs. It is also common to have a combination of heart problems known as "tetralogy of Fallot". There are certain facial features that are common in people with Alagille syndrome, like deep-set eyes, a small pointed chin, and a broad forehead. They might also have differences in the way that their eyes developed, but these don’t usually affect their vision. Finally, many people with Alagille syndrome have butterfly-shaped vertebrae, which are the bones in the spinal column.

Your doctor who diagnoses you with Alagille Syndrome will likely recommend make appointments doctors in several different specialties in order to screen for problems which may be seen in this condition. The doctors who commonly see patients with this condition are:

If a pregnancy is at increased risk for Alagille syndrome, prenatal testing can be done as long as the genetic change causing Alagille syndrome in the family is already known. Prenatal testing will be able to tell if the baby has the genetic change causing Alagille syndrome or not, but cannot tell how severe the symptoms will be in a baby with the genetic change.

The facial features of people with Alagille syndrome are highly characteristic. Doctors trained to see these differences can frequently be concerned about Alagille syndrome based on a patient’s facial features and can confirm their idea by asking other medical questions. Typically, people with Alagille syndrome will have a large forehead, eyes that sit deeper in their heads, a pointed chin, and a bigger tip of the nose. If these features are seen in combination with liver disease or heart problems, Alagille syndrome would be highly suspected.

Newborn screening does not test for Alagille syndrome. However, if a newborn starts showing signs of liver problems, his/her doctor may order testing for Alagille syndrome if there are other symptoms as well.

Since there are multiple types of genetic changes that can cause Alagille syndrome (ALGS), there are multiple genetic tests your doctor might order to confirm a diagnosis of ALGS. Since spelling mistakes in JAG1 are the most common cause of ALGS, found in 89% of people with the condition, sequencing (or reading the gene from start to finish) of JAG1 is usually the first genetic test done. If no spelling mistake is found, your doctor might then order a different test to see if there are big pieces of JAG1 missing or added, since that is the next most common cause of ALGS. If there is still no change in JAG1 found, your doctor might order sequencing of NOTCH2 as the last genetic test. It also may be possible to order all these tests at once, but that would be up to you and your doctor to discuss.

As of April 2019, there are multiple clinical research studies currently underway for Alagille syndrome. Some of these studies are looking at new medicines that might help people with Alagille syndrome and some are looking at the symptoms of Alagille syndrome to understand them better. If you are interested in participating in a clinical research study, www.clinicaltrials.gov is a good place to start looking for trials you can participate in. Search for "Alagille syndrome" to read more about the studies looking for participants. You may also search for specific symptoms you have of Alagille syndrome to see if there are research studies for the specific symptoms.

Alagille syndrome can be abbreviated to ALGS.

There is no cure for Alagille syndrome. However, the different symptoms of Alagille syndrome can be treated as best as possible in each patient.

The symptoms of Alagille syndrome can be very different in different people with the condition. Some people will have very mild symptoms, and may never know they have it. Others may have very severe symptoms, requiring a lot of treatment and sometimes surgery. If a person with Alagille syndrome has very severe heart or liver problems, they may need a heart or liver transplant. In people with more severe symptoms, the condition is more dangerous and can be fatal. Alagille syndrome is fatal in about 1 in 10, or 10%, of people with the condition. Death usually occurs because of stroke, heart problems, or liver problems.

Your doctor should be familiar with the specialists you need to see (e.g. gastroenterologist, cardiologist, nephrologist, etc.). They should also help you maintain a healthy diet to help you continue to grow and develop properly.

That depends on whether or not you or your partner have the same genetic change as your child with Alagille syndrome. If one of you has the same genetic change, there is a 1 in 2, or 50%, chance of each of your future children having Alagille syndrome. This does not mean that 50% of your children will have Alagille syndrome, but that each child has a 50% chance of inheriting it.
If neither of you has the same genetic change, the chance of having another child with Alagille syndrome is low, but it is not impossible. It is always possible, but highly unlikely, that the random event that caused the genetic change in your child could happen again. It is also possible that you or your partner is "mosaic" for a genetic change that cause Alagille syndrome. "Mosaic" means that some of the cells in your body have a genetic change and some don’t. If someone is mosaic for a genetic change, there is a chance that they can pass this change on to their children.

About 15% of people with Alagille syndrome will need a liver transplant. There is no way to predict which babies born with Alagille syndrome will need a liver transplant in the future.

Alagille syndrome is inherited in an "autosomal dominant" manner. We each typically have twp copies of every gene in our body. Genes provide instructions to our cells to make the items that our bodies need to grow and function. When there is a change or spelling mistake (also known as a mutation) in a gene, that gene may not work as well as it is supposed to or may not work at all. "Autosomal dominant" inheritance means that a change in one of the two copies of the gene involved in Alagille syndrome is enough to cause the condition. Since we pass on one copy of each gene to our children when we have babies, a person with Alagille syndrome has a 50% chance of passing on the genetic change causing the condition to each of their children.

Alagille syndrome is usually diagnosed by a doctor based on the symptoms a person is having. A diagnosis of Alagille syndrome is made if a person has a low number of bile ducts in their liver as well as at least three of the following symptoms: buildup of bile in the liver, heart defect, differences in the bones (usually the bones of the spinal column), eye changes, and characteristic facial appearance. If someone in the family already was diagnosed with Alagille syndrome, other family members with at least one of these symptoms may be diagnosed with it as well.
Genetic testing is not always necessary to diagnose the condition. Genetic testing can help let other people in the family what their chance of having a child with Alagille syndrome is.

There are many ways to support Alagille syndrome research, including:

If you want to find clinical research on Alagille syndrome, www.clinicaltrials.gov is a good place to start that is currently underway. The Alagile Syndrome Foundation (www.alagille.org) also adds up-to-date articles about results of clinical research trials, if you are more interested in learning about the results of studies that have already been completed. The Childhood Liver Disease Research and Education Network (ChiLDREN) (www.childrennetwork.org) also has information on clinical research studies that they are performing.

The Children’s Hospital of Philadelpphia (CHOP) has an Alagille Syndrome Clinical Care Program dedicated to treating children with Alagille syndrome. This program allows children to see all the specialists they need in one visit. The program also has a strong focus on research into Alagille syndrome.
If Philadelphia is too far for you, contact your local children’s hospital to see if they have recommendations for doctors familiar with Alagille syndrome. The liver center at your local children’s hospital is a good place to start!
http://www.chop.edu/centers-programs/alagille-syndrome-clinical-care-program

Liver transplants are only done in patients with very severe liver problems who may not survive without a new liver. It is a major surgery. There can be complications of the surgery, some of which can be life-threatening. The 1-year survival rate after a liver transplant in patients with Alagille syndrome is about 87%. This means that 87% of patients with Alagille syndrome who had a liver transplant were alive 1 year after their transplant. This is somewhat lower than the 1-year survival rate for people who had a liver transplant but do not have Alagille syndrome, which is 96%. The difference is probably due to the fact that people with Alagille syndrome usually also have problems with their heart or kidneys, making the surgery more dangerous.

It was first though that about 1 in 70,000 babies are born per year with Alagille syndrome. However, there might actually be more people with Alagille syndrome who have the condition, but are not diagnosed, if their symptoms are very mild. Alagille syndrome may occur in as many as 1 in 30,000 babies.

Up to 97% of people with Alagille syndrome will have some kind of heart difference. This may be as mild as a difference in the way that the heart beats that causes no problems (also known as a "benign heart murmur") or as severe as physical differences that require a heart transplant. The most common heart problem is called "pulmonic stenosis", which means that the blood vessels carrying blood from the heart to the lungs are too narrow. After that, the most common complex heart problem is called "tetralogy of Fallot". Tetralogy of Fallot is a combination of 4 specific physical differences in the heart.

The clinical sensitivity of the test, meaning the chance that a test will find a gene change/mutation in someone who has Alagille syndrome, is about 95%. This means that out of everyone in the world with clinical diagnosis of Alagille syndrome, 95% of them will have a gene change/mutation found on the genetic testing. In other words, 5% of people with Alagille syndrome will not have a gene change/mutation picked up by the test. False positives, meaning a gene change/mutation is found when there actually is not one, are rare.

A blood or saliva test works well for genetic testing for Alagille syndrome. It is not necessary to get a biopsy to do this testing.

While liver disease is one of the most common symptoms of Alagille syndrome, not everyone with the condition will have liver disease. Some people with Alagille syndrome will only have heart problems or the characteristic facial features of the condition.

People with Alagille syndrome should avoid contact sports like football, especially if they have chronic liver disease, a large spleen, or problems with their blood vessels. This is because getting hit or injured can cause severe damage to the body. As well, people with liver disease should avoid drinking alcohol because it can cause more liver damage.

Typically, the differences in the eyes of people with Alagille syndrome do not cause severe vision loss or blindness. The differences in the eyes of people with Alagille syndrome are mostly differences in the way that the eye developed, but don’t usually affect how well the person can see. This means that the eye differences mostly help doctors diagnose a person with Alagille syndrome and don’t usually cause any problems for the person.

Because of the problems with getting enough bile into the digestive system, patients with Alagille syndrome are usually unable to get enough fat and fat-soluble vitamins (vitamins A, D, E, and K). This can lead to problems with growth and development. Infants with Alagille syndrome may be put on a special formula to help them absorb more fats. Also, patients may need to take vitamin supplements to make sure they are getting enough of them. If you are concerned about your child’s diet, talk to your doctor or a nutritionist.

Currently, it appears that there is no difference in symptoms of people with JAG1 mutations compared to NOTCH2 mutations. However, the number of people reported with Alagille syndrome due to NOTCH2 mutations is very small, so it is hard to determine if there is a difference between NOTCH2 and JAG1 mutations in Alagille syndrome.

Alagille syndrome is known to have variable expressivity. "Variable expressivity" means that the symptoms of the condition can be very different from one person to the next. They can even be very different in members of the same family who have the same gene change causing Alagille syndrome. For example, some people with Alagille syndrome have severe liver disease and require a liver transplant. Others have no liver problems, and might just have the characteristic facial features.

There are a few very specific genetic changes in NOTCH2 that cause a condition called Hajdu-Cheney syndrome (also known as serpentine fibula polycystic kidney syndrome). This syndrome causes breakdown of the bones, characteristic facial appearance, cysts (fluid filled sacs) in the kidneys, cleft palate, and heart problems.

There are not any other conditions that we know of that are caused by genetic changes in JAG1. However, some people with changes in JAG1 don’t have all the symptoms of Alagille syndrome, and may not even have enough symptoms to be diagnosed by their doctors with this condition. For example, there have been multiple people reported with JAG1 gene changes who only have heart problems.

If a parent has Alagille syndrome, they can pass it on to their children. There is a 1 in 2, or 50%, chance of each child having Alagille syndrome. That does not mean that half of the parent’s children will have Alagille syndrome, but that each child has a 50% chance of inheriting it. About 30-50% of children with Alagille syndrome have a parent with the condition. In other cases, it may be that the child affected with the condition is the first person in the family to have the gene change.

A fetal echocardiogram (a detailed ultrasound of the baby’s heart) can sometimes pick up differences in the structure of the baby’s heart. This echocardiogram can be done if you know your baby is at an increased risk of having Alagille syndrome (maybe because one of the parents has the condition or you already have a child with Alagille syndrome). It is important to remember that a normal echocardiogram does not mean the baby definitely does not have Alagille syndrome. Also, the other symptoms of Alagille syndrome (liver problems, eye problems, facial features, butterfly veterbrae) are very unlikely to be seen on an ultrasound.

A child can be the first person in the family to be born with Alagille syndrome. This is called "de novo", which means "new". About 50-70% of children are born with de novo Alagille syndrome. In other words, most children born with Alagille syndrome do not have parents with the condition.

Alagille syndrome is usually treated symptom by symptom.

While "Alagille syndrome" is the most common name for this condition, there are many other names that people use when talking about Alagille syndrome. These names include:

There are many groups that provide information and support to people with Alagille syndrome. Some of these support organizations are listed below.

The Alagille Syndrome Alliance (www.alagille.org) is a good place to start if you are looking for support. They host events every three years to help families connect with each other.

The Childhood Liver Disease Research and Education Network (ChiLDREN) (https://childrennetwork.org/) works with multiple groups to support patients and families and to connect people with rare liver conditions. Visit their website to learn more about the support groups they partner with to see if any are right for you.

As far as we know, Alagille syndrome is always a genetic condition. While there are some people with Alagille syndrome that do not have a change or mutation in JAG1 or NOTCH2 found on the genetic tests, that is probably because our tests are not able to find all mutation. These patients very likely have a genetic cause that we just can’t find yet.

Although there are not other conditions that share all of the same health issues as seen in Alagille diseases, there can be overlap of some of the symptoms seen in Alagille. One of the most common symptoms of Alagille syndrome is neonatal cholestasis (where bile backs up into the liver). This can be found unrelated to Alagille as an isolated finding or as a part of another genetic condition. There are also many possible causes of bile duct paucity (too few tubes to carry bile out of the liver). Some of these are also genetic, like Down syndrome, cystic fibrosis, Lysosomal acid lipase deficiency, and metabolic disorders. Your doctor can look for other symptoms to help determine if it is Alagille syndrome or something else.

The eye symptoms of Alagille syndrome are also seen in many other conditions. The most common eye symptom of Alagille syndrome, called posterior embryotoxon (which is a difference in the structure of the eye present at birth), can be seen in many conditions such as Riger syndrome and Bannayan-Riley-Ruvalcaba syndrome (part of the PTEN hamartoma tumor syndrome). It is also seen in 8-15% of the general population.

The most common heart symptom, differences in the pulmonic vascular system (the blood vessels between the heart and lungs), can also be seen in Noonan syndrome, Watson syndrome, LEOPARD syndrome, Down syndrome, and Williams syndrome.
Tetralogy of Fallot, another heart problem, is frequently seen in 22q11.2 deletion syndrome. People with 22q11.2 deletion syndrome can also have butterfly vertebrae and slow growth, 2 other features of Alagille syndrome, but don’t have liver problems.