Alagille Syndrome

What is Alagille syndrome?

Alagille syndrome — also known as Alagille-Watson syndrome, syndromic bile duct paucity and arteriohepatic dysplasia — is an inherited liver disorder that also affects the heart, eyes, bones, kidneys, vasculature and other organs. Individuals with AGS may have:

Characteristic facial features

  • Prominent forehead and pointed chin (giving the face a triangular appearance)
  • Deep-set eyes
  • Straight nose

Liver problems

  • Cholestasis (stoppage of bile flow out of the liver)
  • Jaundice (yellow skin color) caused by the liver's failure to properly process bile
  • Too few bile ducts (intrahepatic bile duct paucity) seen on liver biopsy

Congenital cardiac (heart) abnormalities

  • Peripheral pulmonary stenosis (narrowing of the pulmonary artery)
  • Murmur only
  • Any cardiac anomaly, although the defects typically affect the right side of the heart (e.g. Tetralogy of Fallot)

Ocular (eye) abnormalities

  • Posterior embryotoxon
  • Axenfeld's anomaly

Renal (kidney) abnormalities

  • Renal tubular acidosis
  • Structural renal abnormality

Skeletal abnormalities

  • Butterfly-shaped vertebrae
  • Shortened interpedicular distance
  • Short stature

Causes of Alagille syndrome

Alagille syndrome is predominately caused by changes in a gene called Jagged1 located on chromosome 20. In 3 to 5 percent of cases, the entire gene is deleted (missing) from one copy of chromosome 20. In the majority of cases of Alagille syndrome, there are changes or mutations in the DNA sequence that makes up the Jagged1 gene. In a very small number of cases, less than 1 percent, changes in another gene, Notch 2, result in Alagille Syndrome.

About one-third of children with Alagille syndrome inherit the change in Jagged1 from a parent. In the remaining two-thirds of cases, the mutation in Jagged1 is a new one in that child. Alagille syndrome is an autosomal dominant disorder, which means someone who carries the Jagged1 gene mutation has a 50 percent chance of passing on that mutation to their child.

The effect of having a mutation in Jagged1 can vary widely. Some individuals who inherit a mutation have severe Alagille syndrome, involving heart and liver disease, while others experience only minor manifestations, such as posterior embryotoxon or characteristic facial features.

Genetics and Alagille syndrome

Genes and chromosomes

Genes, which are made up of a substance called DNA, provide the body with a blueprint showing it how to develop and function. Sometimes changes in the genes, called mutations, cause them to function abnormally or not work at all.

Genes are contained within structures called chromosomes, which are found in the nucleus of each cell. We have 23 pairs of chromosomes, for a total of 46. Twenty-two pairs — numbered 1 to 22 (for a total of 44) — are called autosomes. We also have one pair of sex chromosomes, which determine gender. Females have two X chromosomes, while males have one X and one Y.

Each chromosome has one copy of many different genes. Since we have pairs of chromosomes, we have two copies of every gene, one copy from our mother and one from our father. Egg and sperm cells contain 23 chromosomes — or one copy of every gene. Upon fertilization, the developing fetus will inherit two copies of every gene.

Patterns of inheritance

In some cases, when one gene has a mutation and is nonfunctional, the second copy of the gene can compensate. In this case, you would need to have two abnormal copies of the gene to have the disease. Individuals with only one abnormal copy usually don't show any signs of the disease. The disorders that mutations in these types of genes cause are called autosomal recessive. Cystic fibrosis, sickle cell anemia and Tay-Sachs disease are among the conditions inherited this way.

In other cases, if one copy of the gene is functioning abnormally or not at all, the other copy can't compensate. The mutated gene "dominates" over the normally functioning gene, so it is called autosomal dominant. If a condition is autosomal dominant, a person who carries one copy of the gene containing a mutation will usually manifest some signs of that condition. Alagille syndrome is autosomal dominant.

When a person is carrying a mutation in an autosomal dominant gene, each egg or sperm cell has a 50 percent chance of containing the nonfunctioning gene copy and a 50 percent chance of containing the normal copy of the gene. This means that in each pregnancy, the fetus has a 50 percent chance of inheriting the autosomal dominant disorder.

Finding the gene for Alagille syndrome

Since Alagille syndrome was first described in the late 1960s, scientists suspected it was an inherited condition, based on the fact that it often ran in families. Several years ago, researchers noticed individuals with Alagille syndrome were sometimes missing a piece (called a deletion) on chromosome 20. This discovery gave them the idea that the gene that causes Alagille syndrome is probably located on the missing portion of DNA on chromosome 20. By comparing the deletions of different Alagille syndrome patients, these researchers were able to narrow down the region where the gene might be located. They then looked at different genes they knew were located in this region.

In 1997, scientists began studying a gene called Jagged1, named after a similar gene found in fruit flies. Normally, Jagged1 is involved in the normal development of the liver, heart and other organ systems. Researchers looked at the DNA sequence of the Jagged1 gene in people with Alagille syndrome and compared it to the same sequence in unaffected individuals. They found that the people with Alagille syndrome had mutations in this gene and that their affected family members carried the same gene change. Thus, they were able to prove Jagged1 is the gene that causes Alagille.

Recently a small number of patients with Alagille syndrome have been identified who have a mutation in another gene called Notch2 (and not in Jagged1).

For more information about genetics and inheritance, please visit our Division of Human Genetics and Molecular Biology's Web site.

Jagged1 gene analysis

Looking for mutations in a gene is similar to looking for a typo in a book. The genes are the instructions used to make proteins. The DNA in a gene is made up of "base pairs," called A, T, G or C. Three base pairs together are like a word that codes for an amino acid, the basic building blocks of proteins. Each protein in the body can combine with other proteins and may have many different functions. For example, proteins can make up a cell's structure, can be involved in cell-to-cell signaling or can be enzymes necessary for normal metabolism. Each gene is also divided into sections, like chapters in a book, called exons. In between each exon is extra DNA called introns. Jagged1, the gene responsible for Alagille syndrome, is made up of approximately 4,000 base pairs within 26 exons.

In some genetic disorders, each affected person has the same gene change or mutation. In these cases, the lab knows the exact spot to look for the mutation. But in Alagille syndrome, each family usually has a mutation that is different from other families' mutations, although people from the same family do share the same mutation. This makes screening more difficult, because we don't know where in the gene to start looking for the mutation. Like a proofreader searching for a typo in a book, the lab must read each exon to see if it contains a mutation. Sometimes it's in the first "chapter," or exon, but sometimes it might be at the end of the gene. Searching through the entire gene can take a lot of time.

In most cases, scientists study the Jagged1 gene in the laboratory by extracting DNA from a blood sample. Current techniques are able to identify the Jagged1 mutation in approximately 70 percent of children with Alagille syndrome. Once a mutation has been identified in an affected child, parents and other family members can undergo carrier screening.

Prenatal diagnosis can also then be offered to a family. Cells are collected either by amniocentesis or chorionic villus sampling, and scientists test the fetal DNA in those cells. While prenatal diagnosis can determine whether a fetus has inherited a mutation, it can't determine how severe the manifestations are.

Mutation analysis is starting to become available in commercial clinical labs. The types of analyses that are available vary. Some labs are starting to provide total gene sequencing, which has a very high detection rate, but is most expensive. In the Children's Hospital research lab, the mutation detection rate is above 90 percent (Warthen et al., 2005). As with any mutation testing, some patients with Alagille Syndrome will not have a mutation detected by any technique or lab.

Diagnosis of Alagille syndrome

When Alagille syndrome was initially described, a diagnosis required that a person have bile duct paucity in addition to at least three of five major criteria:

  • Cholestasis
  • Characteristic facial features
  • Vertebral abnormalities
  • Eye abnormalities
  • Heart defects

Due to the successful identification of Jagged1 as the gene that causes Alagille syndrome, the diagnostic criteria have been modified. In recent years, it has been recognized that a diagnosis can be made in a person who does not have all of the clinical criteria of Alagille syndrome but does have a mutation in Jagged1. For example, a less severely affected family member who would not meet clinical criteria for AGS but who has the same Jagged1 mutation as a severely affected family member is considered to have AGS.

In the research laboratory at CHOP it is currently possible to identify a mutation in more than 90% of individuals that meet clinical criteria for AGS. A minority (<1%) of patients with Alagille syndrome have a mutation in another gene called Notch2. Mutation testing for this gene is currently only done on a research basis.

Evaluation for Alagille syndrome

Because the manifestations and severity of Alagille syndrome can vary widely, it can often be difficult to diagnose. If your doctor suspects that your child has AGS then he or she may order a number of tests and do certain procedures to rule out other diseases and to help make a diagnosis.

Liver function/gastroenterology (GI)

Most individuals with Alagille syndrome have liver disease, though this may vary in its severity and can also change over time. Children usually develop jaundice in infancy and this is the most common time to undergo evaluation by a gastroenterologist.

An initial evaluation for liver disease will involve a physical examination at which the gastroenterologist will be particularly interested in assessing if the liver and/or spleen are enlarged. Liver function can be assessed by blood tests called liver function tests. These are a group of tests that include ALT, AST, GGT, albumin, bilirubin, conjugated bilirubin and PT/PTT.

If appropriate, further tests may be necessary. These may include an ultrasound of the abdomen, which can help to rule out other causes of jaundice and can assess the degree of enlargement of the liver and spleen. Sometimes a liver biopsy is helpful to make the diagnosis of Alagille syndrome, though this is not mandatory to make the diagnosis. This test is usually performed under conscious sedation and requires a small core of liver tissue being taken with a needle through the skin.

Pancreatic function tests: 72-hour stool collection

Doctors can indirectly assess pancreatic function with a 72-hour stool collection, in combination with a three-day dietary record, to determine how much fat a child is absorbing from the food he or she is eating. Because this collection is usually done at home, you will be given the supplies and instructions you need. All stools are collected in pre-weighed containers for 72 hours and frozen. Everything your child eats during these three days must be weighed and recorded. The laboratory then determines the amount of fat absorbed  (coefficient of fat absorption). Unfortunately, this test cannot distinguish between fat malabsorption due to liver disease and fat malabsorption due to pancreatic diseases.


Your child may also see a cardiologist (a physician who specializes in caring for hearts) who can rule out any mild heart problems.

The cardiologist will perform a complete physical examination and will most likely perform an ECG and echocardiogram. An ECG measures the heart rhythm. The echocardiogram is an ultrasound of the heart and will define the exact structure and function of the heart. Depending upon the results of the examination and these studies, the cardiologist may decide to order other tests or to arrange follow up visits in the future.

Ophthalmologic (Eye)

Many children with Alagille syndrome have an unusual abnormality of the eyes. Posterior embryotoxon, an extra, circular line on the surface of the eye, is the most common eye finding. This requires a specialized eye examination to detect and does not lead to any disturbances in vision. Pigmentary changes of the retina (thin layer of photoreceptors lining the inside wall of the eye) are present in some children with AGS. An ophthalmologist can examine your child's eyes to look for posterior embryotoxon and other eye abnormalities.


X-rays of the spine can help detect "butterfly" vertebrae, the most common skeletal defect associated with Alagille syndrome. A clefting abnormality gives the vertebrae a "flying butterfly" appearance on X-rays. Generally, butterfly vertebrae do not cause any symptoms, but they do help with making a diagnosis.

Genetics evaluation and testing

If your child's physician suspects he or she has Alagille syndrome, your child should see a geneticist (a physician trained in genetics) and a genetic counselor. Most geneticists are trained in dysmorphology, or the study of how the face and body are formed. A geneticist will be able to evaluate your child for the facial features characteristic of Alagille syndrome.

Together, the geneticist and genetic counselor will review the results of the other diagnostic studies (such as eye exam, spine X-rays, etc.), as well as your family history. They will provide you with information about the genetics and inheritance pattern of Alagille syndrome. Based on the information gathered from your family history and genetic testing results, they can also address questions about the chance that future children in your family could be affected with Alagille syndrome.

Liver disease and Alagille syndrome

Most people with Alagille syndrome symptoms will exhibit signs of liver disease in infancy but, because the disorder manifests itself differently from person to person, some carriers of a gene mutation may have no detectable liver disease.

Those with liver disease may experience a wide range of symptoms, most as a result of cholestasis (reduction of bile flow):

  • Jaundice (yellowish skin color) caused by bile buildup in the blood
  • Pruritus (itching), rarely seen before the age of 3 months but most often seen by 3 years
  • Increased serum (blood) bile acid concentration
  • Xanthomas (bumps on skin resulting from fat deposits) usually seen at the elbows, ankles, knees and diaper line
  • Growth failure, seen in 50 to 90 percent of patients

Pruritus and xanthomata can have a significant impact on quality of life. Pruritus can disturb sleep and attention in school. Xanthomata may be cosmetically disfiguring and, depending on their location, may interfere with certain activities.

Bile flow may be stimulated with ursodeoxycholic acid, but in many patients the pruritus continues. Care should be taken to keep the skin hydrated with emollients, and fingernails should be trimmed to avoid skin damage from itching. Baths should be avoided as they dry out the skin and short showers are recommended, especially in winter months. Therapy with antihistamines may provide some relief, but many patients require additional therapy with agents such as rifampin or naltrexone. Biliary diversion has been successful in a limited number of patients but pruritus continues to be an indication for transplantation in some patients.

The severity of liver disease in Alagille syndrome typically peaks by 3 to 5 years of age and often resolves by 7 to 8 years of age. In some people, the hepatic disease will progress to end-stage liver disease and may require liver transplantation. Approximately 15 percent of patients with Alagille syndrome require liver transplantation. We currently have no way of predicting which children who have liver disease in infancy will progress to end-stage liver disease and in which children the cholestasis will resolve.

Heart defects and Alagille syndrome

Approximately 90 percent of children with Alagille syndrome have a heart defect at birth. The severity of the heart defect can range from a simple murmur causing no problems to a major structural heart defect. Most Alagille-related heart defects involve the pulmonary arteries, which carry blood from the right side of the heart to the lungs. The most common defect is peripheral pulmonary stenosis. Other potential structural cardiac defects include:

  • Tetralogy of Fallot (12 percent of cases)
  • Ventricular septal defects (VSD)
  • Atrial septal defects (ASD)
  • Aortic stenosis
  • Coarctation of the aorta

The more severe congenital heart defects may require treatment, including surgical intervention. If your child has Alagille-associated heart problems, his or her doctor will talk with you about treatment options.

Skeletal (bone) problems and Alagille syndrome

The most common skeletal defect found in Alagille syndrome involves the vertebrae (the small bones that make up the spine). These "butterfly" vertebrae have an X-ray appearance of flying butterflies. While butterfly vertebrae are an important way doctors recognize the diagnosis of AGS in a child, they do not cause any medical problems and therefore do not require treatment.

Because children with Alagille syndrome may develop fat-soluble vitamin (A, D, E and K) deficiencies, it is important to have the vitamin D level in their blood checked. If children are deficient in vitamin D and are not adequately supplemented, they can develop rickets. Rickets is a disease of infants and children that disturbs normal bone formation (ossification). Common features of rickets include softness of the infant's skull (craniotabes) and enlargement of the front end of the ribs (creating the "rachitic rosary"). As a child with rickets begins to walk, he or she may have bowed legs. Rickets can be treated with large doses of vitamin D.

Some children with AGS have frequent long bone fractures. The reason why children with AGS may be prone to fractures is unknown, although several factors may include: abnormally-shaped bones due to the defect in JAG1, poor calcium intake and/or calcium malabsorption and decreased physical activity. A doctor and/or dietitian can help determine if a child with AGS is consuming enough calcium and if calcium supplementation is needed.

The eyes and Alagille syndrome

The eye problems associated with Alagille syndrome primarily involve the anterior (front) chamber of the eye and the retina. Approximately 90 percent of children with Alagille have posterior embryotoxon, which also occurs in 8 to 15 percent of the general population. Some children also experience retinal pigmentary (color) changes. While scientists initially thought these changes were the result of dietary deficiencies, these changes have now been reported in individuals with Alagille syndrome who have normal levels of vitamins A and E.

Posterior embryotoxon, commonly associated with Alagille syndrome, causes no medical problems on its own, and therefore doesn't require treatment.

Rarer eye problems associated with Alagille syndrome may require treatment.

The kidneys and Alagille syndrome

Approximately 40 to 50 percent of children with AGS have renal (kidney) disease. A variety of structural, function and acquired renal disorders have been identified in children with AGS including:

  • Solitary kidney
  • Ectopic kidney
  • Small kidney
  • Unilateral and bilateral multicystic kidneys
  • Dysplastic kidneys
  • Horseshoe kidney
  • Renal tubular acidosis

These conditions require a combination of blood tests, ultrasound and urine tests for diagnosis and evaluation.
These disorders are not usually associated with renal failure. Renal tubular acidosis is an important potential contributor to poor growth in Alagille syndrome. If your child is suspected of having kidney disease, he or she may be referred to a pediatric nephrologist for evaluation.

The pancreas and Alagille syndrome

It is well-documented that Alagille syndrome affects multiple organs, such as the liver, heart, kidneys and skeleton, but we are just starting to explore how it affects the pancreas. Researchers previously thought that the poor growth and malnutrition associated with this disorder were only a result of bile flow stoppage (also called cholestasis), which in turn contributes to the body's inability to absorb fat. Now medical professionals are beginning to realize that the pancreas may also be playing a role in fat malabsorption in AGS.

The pancreas is important for the digestion and absorption of nutrients. It is made up of two separate parts, each with a unique function. The first, the endocrine pancreas, makes hormones — including insulin and glucagon — that help regulate the body's sugar balance. The second part, known as the exocrine pancreas, makes enzymes that help digest food and release the bicarbonate that neutralizes stomach acid. If the pancreas is not making enough of these enzymes and acid buffers, a person is said to be pancreatic insufficient.

Children who are pancreatic insufficient do not properly absorb fat from food, which is called fat malabsorption, and excrete fat in their stools. Stools of children with fat malabsorption are often loose, greasy and not well-formed. Based upon past and ongoing studies of Alagille patients, we estimate between 30 and 40 percent of children with Alagille syndrome are pancreatic insufficient, which may, in turn, contribute to their poor nutrition and growth.

Pancreatic exocrine function can help determine if your child is pancreatic insufficient; it can be tested both directly and indirectly.

A healthy child older than 6 months should absorb more than 93 percent of his or her dietary fat. It is not abnormal for healthy infants to excrete up to 15 percent of dietary fat. If a child is absorbing less than 93 percent, he or she is said to be fat-malabsorbing. Pancreatic insufficiency is one cause of fat malabsorption. Liver disease can also be a contributing factor.
If tests determine your child is pancreatic insufficient, he or she will receive pancreatic enzyme supplementation. Pancreatic enzymes supplements, taken before meals, help to digest or break down food so the body can absorb nutrients.

Pancreatic function tests: 72-hour stool collection

Doctors can indirectly assess pancreatic function with a 72-hour stool collection, in combination with a three-day dietary record, to determine how much fat a child is absorbing from the food he or she is eating. Because this collection is usually done at home, you will be given the supplies and instructions you need. All stools are collected in pre-weighed containers for 72 hours and frozen. Everything your child eats during these three days must be weighed and recorded. The laboratory then determines the amount of fat absorbed (coefficient of fat absorption). Unfortunately, this test cannot distinguish between fat malabsorption due to liver disease and fat malabsorption due to pancreatic diseases.

Vascular problems and Alagille syndrome

Intracranial bleeding (bleeding within the skull) is the most dangerous central nervous system complication of Alagille syndrome and is a major cause of morbidity and mortality. It occurs in approximately 15 percent of people with AGS, and in 30 to 50 percent of these events the bleed is fatal. The majority of these events are spontaneous, although some have occurred after minor head trauma. It is not possible to predict who is at risk for developing a bleed. In addition to bleeding within the head, blood vessel problems such as aneurysms (dilatations) and stenoses (narrowings) can also be seen elsewhere in the body, such as kidney vessels and the aorta. At CHOP we recommend a baseline MRI of the brain in all young children with Alagille syndrome.

In the event of a head injury (for instance, a fall), a medical evaluation is recommended and imaging of the brain (by CT or MRI) may be warranted if there are any suspicious signs or symptoms.

Vitamin supplementation for children with Alagille syndrome

Most children with Alagille syndrome need to take vitamin supplements. Because children with Alagille syndrome have difficulty absorbing fat, they may develop fat-soluble vitamin (A, D, E and K) deficiencies if they do not receive proper supplementation. They may also require extra calcium and zinc. The best way for a child with Alagille syndrome to receive the vitamins that he or she needs is to take separate vitamin supplements for each vitamin. Blood levels of vitamins should be monitored and supplements should be adjusted accordingly. Be sure to talk to your child's doctor about what vitamin supplements your child may need. Also, don't give give your child any additional vitamins without first checking with the healthcare team, because too much Vitamin A can be toxic to the liver.

  • Vitamin A
  • Vitamin D
  • Vitamin E
  • Vitamin K
  • ADEK
  • Calcium
  • Zinc
  • Vitamin A

Vitamin A is required for normal vision, cellular differentiation, reproduction, growth and proper immune function. Vitamin A is found primarily in selected foods of animal origin, especially liver and dairy products including whole milk, cheese and butter, as well as fish such as tuna and sardines. Signs and symptoms of vitamin A deficiency include growth retardation, increased susceptibility to infection and night blindness. Vitamin A can be toxic to the liver so individuals with AGS need to be careful about oversupplementation Careful monitoring of blood levels is essential to avoid toxicity.

Vitamin D

Vitamin D is extremely important for bone health. Without enough vitamin D, children's bones can become thin, brittle and soft and rickets can develop. Vitamin D is found in foods such as milk and fatty fishes and can also be made by the body when it is exposed to sunlight. There are different forms of vitamin D and the proper form for children with cholestasis is cholecalciferol. Vitamin D levels (25 [OH] D) should be checked every few months, and supplementation should be adjusted to make sure that levels are at the high end of normal. Your child's vitamin D levels should also be checked during different seasons, because levels tend to be higher in the summer due to more sunlight exposure.

Vitamin E

Vitamin E protects cells against the effects of free radicals, which are potentially damaging by-products of the body's metabolism. Vitamin E deficiency can cause decreased reflexes, weakness, wide gait (walking with the legs far apart) and hemolytic anemia. Children with cholestasis on large doses of vitamin E (either alpha tocopherol or alpha tocopherol acetate) can still have a vitamin E deficiency. The best vitamin E form for preventing or reversing this deficiency is the liquid form: tocopheryl polyethylene glycol 1000 succinate (TPGS), because the body absorbs it more readily. TGPS also enhances vitamin D absorption. Your child's vitamin E levels should be checked regularly.

Vitamin K

Vitamin K is important for bone health and clotting. Children with vitamin K deficiency usually bruise and bleed more easily. Vitamin K is found in cabbage, cauliflower, spinach, and other green leafy vegetables, cereals, soybeans and other vegetables. Children whose blood clotting times can't be normalized with oral vitamin K may need intramuscular (into the muscle) vitamin K injections.


ADEK is a multivitamin supplement designed for people with malabsorptive conditions. It comes in pills or liquid and is all-in-one formula contains high levels of fat-soluble Vitamins A, D, E and K in water-miscible form, plus water-soluble vitamins and zinc.


Calcium is the mineral that makes up bones and keeps them strong. If you don't get enough calcium from the food you eat, your body automatically takes the calcium you need from your bones. Calcium is most widely found in dairy foods but is also fortified foods including certain brands of orange juices. Fractures are common in children with Alagille syndrome. If your child has low calcium intake, low bone density and/or severe fat malabsorption, he or she should take calcium supplements. A bone density test (called a DEXA scan) — a noninvasive test — can measure your child's bone health and help determine if he or she needs more calcium.


Zinc is an essential mineral that is found in almost every cell. Zinc supports a healthy immune system, is needed for wound healing and helps maintain a sense of taste and smell. Zinc also supports normal growth and development during childhood and adolescence. Zinc deficiency most often occurs when zinc intake is inadequate or poorly absorbed, when there are increased losses of zinc from the body, or when the body's requirement for zinc increases. Signs of zinc deficiency include growth retardation, hair loss, diarrhea, delayed sexual maturation and loss of appetite. Your child may have his or her blood zinc levels tested. While these levels aren't very effective at indicating zinc deficiency, currently there is no better alternative. If your child's zinc levels are low, he or she may benefit from zinc supplementation.

Growth and nutrition issues in Alagille syndrome

Growth failure, delayed puberty and malnutrition are common in children with Alagille syndrome. Children with AGS have worse growth failure than children with other chronic liver diseases, such as biliary atresia. Although the exact cause of this growth failure is unknown, possible causes are:

  • Fat malabsorption (inability to absorb fat) from the liver and/or the pancreas
  • Insufficient calorie or nutrient intake
  • The gene defect in Jagged1

Proper nutrition for children with Alagille syndrome is necessary to prevent and treat growth failure and to prevent and treat nutritional deficiencies. Children with AGS may be evaluated and monitored by a registered dietitian (RD) to assess their growth and nutritional status as well as to make individualized dietary recommendations. At The Children's Hospital of Philadelphia, these services are provided by the Nutrition Services Program. Children who are unable to consume adequate calories or who have poor growth may require a nasogastric tube (NG tube) or gastrostomy tube (G-tube) to improve their nutrition and growth. Children's Hospital provides these services through its Pediatric Enteral Access Center.

Children with Alagille syndrome who undergo liver transplantation do not have as much "catch-up" growth after transplantation as children with other liver diseases, which may suggest that poor growth is due to the primary gene defect in Jagged1. Unlike other pediatric liver diseases, Alagille syndrome can also involve organ systems — such as the kidney or heart — which may impair growth. More research is needed to learn why children with AGS do not grow as much after liver transplantation as children with other liver diseases grow.

Your child's physician and dietitian will work with your child to ensure that he or she gets the best possible nutrition to support growth and development. It is important for children with AGS to consume adequate calories and maintain normal serum levels of vitamins.

Dietary intake for children with Alagille syndrome

Children with Alagille syndrome should consume high-calorie diets because of their poor growth and reduced ability to absorb fat. A child with Alagille syndrome may excrete as much as 50 percent of dietary fat in his or her stool. Your child's physician may prescribe a formula or nutritional supplement with medium-chain triglycerides because children with Alagille syndrome are better able to absorb this type of fat.

Some parents say that high-fat foods give their child loose greasy stools, so they put their child on a low-fat diet. This is not generally recommended, because fat is the most concentrated source of calories. If your child has to be on a low-fat diet because he cannot tolerate fat, you will need to make an effort to ensure your child is consuming enough calories to grow. A registered dietitian (RD) can assess your child's growth and diet, then help make dietary recommendations.

Developmental issues and Alagille syndrome

In the initial reports of Alagille syndrome, intellectual disabilities were described as being a common feature. More recent studies have demonstrated mild delays in gross motor skills in 16 percent of patients and mild intellectual disabilities in very few. The decreased prevalence of learning disabilities in recent studies most likely represents earlier disease recognition and more aggressive medical and nutritional intervention, particularly vitamin supplementation. If your child is suspected of having a developmental delay, he or she may be referred to a developmental pediatrician for evaluation.

Frequently asked questions about Alagille syndrome

Is Alagille syndrome always inherited?

No. In about half of the Alagille syndrome cases, the child inherits the gene mutation from a parent. The other half are what we call "new mutations," meaning the mutation occurred in the gene, either when an egg or sperm cell was being made or in one of the first cells of the developing embryo. While parents whose children are diagnosed with Alagille syndrome often recall things that happened during the pregnancy, such as falls or exposures to chemicals or medications, it's important to remember that nothing you do can cause or prevent these new mutations from occurring; they happen as a part of the natural cell division process.

A person who has Alagille syndrome as a result of a new mutation has a 50 percent chance of passing that mutation on to his or her offspring. The child who does inherit a Jagged1 mutation will have some Alagille syndrome manifestations, but there is no way to predict how severely affected he or she will be. The severity of Alagille syndrome varies widely in children with Jagged1 mutations, even among members of the same family.

How do I know if I carry a Jagged1 mutation?

The first step is to identify the mutation in the family member who is known to have Alagille syndrome. Once that individual's mutation is identified, other family members can be tested.

However, in some families, current testing techniques are unable to identify a Jagged1 mutation in the affected person, making it more difficult to predict the recurrence risk for parents or other family members. In these cases, these family members should undergo clinical studies and consultations to be assessed for subtle Alagille syndrome symptoms, including:

  • An ophthalmologic examination to look for posterior embryotoxon
  • Liver function testing to look for liver enzyme elevations
  • An X-ray of the spine to look for butterfly vertebrae
  • A consultation with a cardiologist or internist to rule out mild cardiac symptoms
  • A consultation with a geneticist trained in dysmorphology to evaluate for characteristic facial features

Unfortunately, interpreting this clinical workup can sometimes be difficult, because some of these same findings are found in people who don't have Alagille syndrome. A clinical geneticist or genetic counselor familiar with Alagille syndrome should review the results of the workup of a parent or relative to try to determine the recurrence risk for the individual.

If a parent isn't a Jagged1 or Notch2 mutation carrier, is he or she still at risk of having another child with Alagille syndrome?
If the parents of a child with Alagille syndrome are found not to carry the gene mutation or deletion found in their child, they have a very small chance of having another child with Alagille syndrome. Although this chance is very low, it's not zero. If a new mutation occurs in an egg or sperm cell, it's also possible it's present in several other egg or sperm cells. If one of these other cells containing the mutation or deletion is used in a fertilization, the fetus would inherit the Jagged1 mutation. When a subset of cells contains the same gene mutation or deletion like this, it's called to as gonadal mosaicism. Gonadal mosaicism is a rare event, but it does occur. The risk for parents of a child with a new mutation to have another child with the same mutation is estimated at about 1 percent.

Is there prenatal testing for Alagille syndrome?

Once a mutation or deletion is identified in a child with Alagille syndrome, parents and other family members can be tested for the gene change. If a person is found to carry the mutation or deletion, he or she has a 50 percent chance of passing it on in a pregnancy. During a pregnancy, the fetus could be tested for the mutation with standard prenatal testing (chorionic villus sampling or amniocentesis). But while prenatal testing can determine if the fetus has inherited a Jagged1 mutation or deletion, it can't predict the severity of the disorder, which might range from serious cardiac and liver disease to more benign manifestations. Other prenatal tests — such as a fetal echocardiogram designed to look for severe heart defects — may offer some further information, but they are also limited.

Why does the severity of Alagille symptoms vary so much?

Doctors have noted that the severity of Alagille syndrome can vary widely from person to person. Even when they have compared affected siblings or an affected parent to his or her child, they recognized that Alagille manifestations can be very different. This became more evident once it became possible to test the family members of affected individuals for gene mutations. We have found that many people with Jagged1 mutations would not have been suspected to have Alagille syndrome. They might have one or two less-serious findings — such as posterior embryotoxon, butterfly vertebrae, innocent heart murmurs or characteristic facial features — that never needed medical attention.

Although we now know that Jagged1 is the gene that causes Alagille syndrome in most cases, we don't yet understand what makes this disorder so variable, even within families. It is possible that Jagged1's function is affected by its interactions with other genes and environmental factors.

What causes the itching in Alagille syndrome, and what can relieve it?

The bile buildup in the blood causes the itching that children with Alagille syndrome experience. Your child's doctor may prescribe medications such as ursodeoxycholic acid, to increase bile flow, which will in turn relieve the itching. He or she may also recommend an antihistamine medication. Be sure to keep your child's skin moist with softening lotions (ask your doctor for a recommendation) and keep his or her fingernails trimmed.

Why do children with Alagille syndrome experience poor growth?

We don't fully understand why children with Alagille syndrome experience growth failure. Possible causes include insufficient calorie intake, fat malabsorption (decreased ability to absorb fat) due to liver or pancreatic disease, congenital (present at birth) defects (such as heart disease) and the defect in the Jagged1 gene.

What causes children with Alagille syndrome to develop xanthomas?

The severe high cholesterol in AGS leads to cholesterol depositions in the skin. In children with Alagille syndrome, spontaneous improvement in bile flow often occurs in children after 3 years of age and this leads to a reduction in lipids and xanthomas.

Are children with Alagille syndrome at risk for developing a heart attack later in life due to their high cholesterol?

It is well known that high cholesterol in adults increases the risk of developing heart disease. The impact of high cholesterol in children with Alagille syndrome on their risk of heart attack later in life is not known though it has not been observed to be a problem. Families often ask about putting their children on statin drugs which are used to lower cholesterol in adults. These should be used cautiously because they can cause liver problems.

Should children with AGS consume a low-fat, low-cholesterol diet?

No. Most children with AGS need to consume high calorie diets to optimize growth and make up for the excess fat lost in their stools. Dietary recommendations for children with AGS will depend on several factors including stage and severity of liver disease and other organ involvements (such as kidney disease). Therefore, specific recommendations should come from your child's physician and/or dietitian. However, because fat is the most concentrated source of calories, it is difficult to consume a high calorie diet that is low in fat and it is not recommended that children with AGS restrict fat. Also a low cholesterol diet is not necessary. People get cholesterol in two ways. The body, mainly the liver, produces varying amounts of cholesterol and foods can also contain cholesterol. Because children with AGS have a problem with their liver, eliminating cholesterol from the diet will not correct the problem.