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Alagille syndrome

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Other Names:
Hepatic ductular hypoplasia; Watson Alagille syndrome; Alagille-Watson syndrome; Hepatic ductular hypoplasia; Watson Alagille syndrome; Alagille-Watson syndrome; Cholestasis with peripheral pulmonary stenosis; Arteriohepatic dysplasia; Paucity of interlobular bile ducts; Cardiovertebral syndrome; Watson-Miller syndrome; Hepatofacioneurocardiovertebral syndrome See More
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Alagille syndrome is a genetic syndrome that can affect the liver and other parts of the body. The liver problems result from having fewer small bile ducts than normal in the liver. This leads to bile building-up inside the liver, which in turn causes liver scarring and damage.[1] Signs and symptoms of Alagille syndrome are generally noticed in infancy or early childhood. Type of symptoms and severity varies greatly, even among people in the same family, so that in some cases the symptoms are severe, and in others, very mild. The liver problems may be the first symptoms of the syndrome, and may include yellow color of the skin and whites of the eyes (jaundice); itchy skin; bumps on the skin caused by deposits of cholesterol and fats (xanthomas); pale, loose bowel movements; and poor growth. [1][2] Alagille syndrome can also affect other parts of the body including the heart, brain, kidneys, blood vessels, eyes, face, and skeleton. People with Alagille syndrome may have distinctive facial features too, including a broad, prominent forehead, deep-set eyes, and a small, pointed chin.[1]

Alagille syndrome is caused by changes or mutations in the JAG1 and NOTCH2 genes.  Inheritance is autosomal dominant. However, in about half of cases the mutation occurs as a new change ("de novo") without being inherited from either parents.[3] While there is no known cure for Alagille syndrome, there are treatments that can help control symptoms. Possible treatments may include medication that increases the flow of bile and careful management of diet to minimize nutrition and vitamin related problems. In severe cases, a liver transplant may be necessary.[1]
Last updated: 10/20/2017
Alagille syndrome is a complex multisystem disease involving the liver, brain, heart, eyes, face, and skeleton.[4] Symptoms typically present in infancy or early childhood. The severity of the syndrome varies greatly, even within the same family.[3][4] Symptoms range from so mild as to go unnoticed to severe enough to require heart and/or liver transplants. Symptoms may include:[2][3][4][5]  
  • Liver problems: One of the major features of Alagille syndrome is liver damage caused by abnormalities in the bile ducts. These ducts carry bile, which helps to digest fats, from the liver to the gallbladder and small intestine. In Alagille syndrome, the bile ducts may be narrow, malformed, and reduced in number. This results in a build-up of bile causing scarring that prevents the liver from working properly. This may lead to jaundice, itchy skin, and deposits of cholesterol in the skin (xanthomas).
  • Nutrition problems: Since bile is important for the digestion and absorption of fat and fat-soluble vitamins, people with Alagille syndrome may have a hard time getting enough calories and may develop Vitamin A, D, E and/or K deficiencies. Calcium and zinc deficiencies may also be associated with Alagille syndrome. Many people with Alagille syndrome continue to have nutrition problems even after a liver transplant, suggesting that other factors of the syndrome may play a role. Malnutrition can lead to slow growth, delayed puberty and other health concerns. 
  • Heart problems: Alagille syndrome is also associated with several heart problems, including impaired blood flow from the heart into the lungs (pulmonic stenosis). Other associated heart-related problems include a hole between the two lower chambers of the heart (ventricular septal defect) and a combination of heart defects called tetralogy of Fallot.
  • Distinctive facial features: People with Alagille syndrome may have distinctive facial features, such as  a broad, prominent forehead; deep-set eyes; and a small, pointed chin. 
  • Neurologic problems: Some people with Alagille syndrome may have intellectual disabilities and developmental delay.
  • Vascular problems: Alagille syndrome can be associated with abnormalities of the blood vessels in the head and neck, which can lead to spontaneous or injury-induced bleeding in the skull or brain, or a stroke. Alagille syndrome can also cause narrowing (stenosis) or bulging (aneurysm) of other blood vessels in the body.
  • Kidney problems: Some children may have impaired kidney function such as kidney artery stenosis, lipoid nephrosis, or glomerulosclerosis. 
  • Bone problems: People may have  an unusual butterfly shape of the bones of the spinal column (vertebrae) but this shape almost never causes any problems with the function of the nerves in the spinal cord. However, Vitamin D deficiency can lead to rickets or weakened bones and poor growth. Calcium deficiency and other features of Alagille syndrome can also lead to poor growth, abnormally shaped bones, and increased risk of broken bones.  
  • Eye problems: Eye abnormalities are common in Alagille syndrome, but for the most part do not require treatment and do not cause vision loss. The most common eye finding is an extra, circular line on the surface of the eye, called a posterior embryotoxon, that can be detected during a specialized eye examination. Although about 90% of people with Alagille syndrome have this eye finding, so do up to 15% of people who do not have this syndrome. Other eye findings may include Axenfeld anomaly, in which strands of the colored part of the eye (iris) are abnormally attached to the cornea, and color changes of the retina (retinal pigmentary changes).
  • Pancreatic insufficiency: Alagille syndrome can cause pancreatic insufficiency. People whose pancreas does not produce enough enzymes to help digest food do not properly absorb fat from food (fat malabsorption) and excrete fat in their bowel movements. Pancreatic insufficiency can cause poor nutrition and growth and therefore is believed to play a larger role than first suspected in the nutritional problems for people with Alagille syndrome. 

More information about the symptoms associated with Alagille syndrome can be found on the Children's Hospital of Philadelphia (CHOP) Alagille Syndrome information page and GeneReviews Alagille Syndrome Report.

Last updated: 10/20/2017

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

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HPO ID
80%-99% of people have these symptoms
Cholestasis
Slowed or blocked flow of bile from liver
0001396
Corneal dystrophy 0001131
Failure to thrive
Faltering weight
Weight faltering
[ more ] 		0001508
Hepatomegaly
Enlarged liver
0002240
Reduced number of intrahepatic bile ducts 0006571
Ventricular septal defect
Hole in heart wall separating two lower heart chambers
0001629
30%-79% of people have these symptoms
Butterfly vertebral arch 0004617
Coarse facial features
Coarse facial appearance
0000280
Frontal bossing 0002007
Intrauterine growth retardation
Prenatal growth deficiency
Prenatal growth retardation
[ more ] 		0001511
Long nose
Elongated nose
Increased height of nose
Increased length of nose
Increased nasal height
Increased nasal length
Nasal elongation
[ more ] 		0003189
Pointed chin
Pointy chin
Small pointed chin
Witch's chin
[ more ] 		0000307
Protruding ear
Prominent ear
Prominent ears
[ more ] 		0000411
Round face
Circular face
Round facial appearance
Round facial shape
[ more ] 		0000311
Spina bifida occulta 0003298
Telangiectasia of the skin 0100585
Vertebral segmentation defect 0003422
5%-29% of people have these symptoms
Abnormal pupil morphology
Abnormality of the pupil
Pupillary abnormalities
Pupillary abnormality
[ more ] 		0000615
Abnormality of the ribs
Rib abnormalities
0000772
Abnormality of the ureter 0000069
Atrial septal defect
An opening in the wall separating the top two chambers of the heart
Hole in heart wall separating two upper heart chambers
[ more ] 		0001631
Brachycephaly
Short and broad skull
0000248
Clinodactyly of the 5th finger
Permanent curving of the pinkie finger
0004209
Cryptorchidism
Undescended testes
Undescended testis
[ more ] 		0000028
Deeply set eye
Deep set eye
Deep-set eyes
Sunken eye
[ more ] 		0000490
Delayed puberty
Delayed pubertal development
Delayed pubertal growth
Pubertal delay
[ more ] 		0000823
Delayed skeletal maturation
Delayed bone maturation
Delayed skeletal development
[ more ] 		0002750
Downslanted palpebral fissures
Downward slanting of the opening between the eyelids
0000494
Flat face
Flat facial shape
0012368
Hypertelorism
Wide-set eyes
Widely spaced eyes
[ more ] 		0000316
Hypertension 0000822
Hypoplasia of the ulna
Underdeveloped inner large forearm bone
0003022
Intellectual disability, mild
Mental retardation, borderline-mild
Mild and nonprogressive mental retardation
Mild mental retardation
[ more ] 		0001256
Keratoconus
Bulging cornea
0000563
Micrognathia
Little lower jaw
Small jaw
Small lower jaw
[ more ] 		0000347
Nephrotic syndrome 0000100
Peripheral pulmonary artery stenosis
Narrowing of peripheral lung artery
0004969
Renal hypoplasia/aplasia
Absent/small kidney
Absent/underdeveloped kidney
[ more ] 		0008678
Short distal phalanx of finger
Short outermost finger bone
0009882
Short philtrum 0000322
Specific learning disability 0001328
Strabismus
Cross-eyed
Squint
Squint eyes
[ more ] 		0000486
1%-4% of people have these symptoms
Duplicated collecting system 0000081
Focal segmental glomerulosclerosis 0000097
Hepatic failure
Liver failure
0001399
Renal artery stenosis
Narrowing of kidney artery
0001920
Renal dysplasia 0000110
Renal tubular acidosis
Accumulation of acid in body due to kidney problem
0001947
Stage 5 chronic kidney disease 0003774
Vesicoureteral reflux 0000076
Percent of people who have these symptoms is not available through HPO
Abnormal anterior chamber morphology 0000593
Areflexia
Absent tendon reflexes
0001284
Autosomal dominant inheritance 0000006
Axenfeld anomaly 0001492
Band keratopathy 0000585
Broad forehead
Increased width of the forehead
Wide forehead
[ more ] 		0000337
Cataract
Clouding of the lens of the eye
Cloudy lens
[ more ] 		0000518
Chorioretinal atrophy 0000533
Cirrhosis
Scar tissue replaces healthy tissue in the liver
0001394
Coarctation of aorta
Narrowing of aorta
Narrowing of the aorta
[ more ] 		0001680
Depressed nasal bridge
Depressed bridge of nose
Flat bridge of nose
Flat nasal bridge
Flat, nasal bridge
Flattened nasal bridge
Low nasal bridge
Low nasal root
[ more ] 		0005280
Elevated hepatic transaminase
High liver enzymes
0002910
Exocrine pancreatic insufficiency
Inability to properly digest food due to lack of pancreatic digestive enzymes
0001738
Hemivertebrae
Missing part of vertebrae
0002937
Hepatocellular carcinoma 0001402
Hypercholesterolemia
Elevated serum cholesterol
Elevated total cholesterol
Increased total cholesterol
[ more ] 		0003124
Hypertriglyceridemia
Increased plasma triglycerides
Increased serum triglycerides
Increased triglycerides
[ more ] 		0002155
Incomplete penetrance 0003829
Infantile onset
Onset in first year of life
Onset in infancy
[ more ] 		0003593
Macrotia
Large ears
0000400
Microcornea
Cornea of eye less than 10mm in diameter
0000482
Multiple small medullary renal cysts 0008659
Myopia
Close sighted
Near sighted
Near sightedness
Nearsightedness
[ more ] 		0000545
Papillary thyroid carcinoma 0002895
Pigmentary retinopathy 0000580
Posterior embryotoxon 0000627
Prolonged neonatal jaundice
Prolonged yellowing of skin in newborn
0006579
Renal hypoplasia
Small kidneys
Underdeveloped kidneys
[ more ] 		0000089
Stroke 0001297
Tetralogy of Fallot 0001636
Triangular face
Face with broad temples and narrow chin
Triangular facial shape
[ more ] 		0000325
Upslanted palpebral fissure
Upward slanting of the opening between the eyelids
0000582
Showing of 82 |
Last updated: 7/1/2020
Many doctors may be necessary for the best management of Alagille syndrome, including specialists in medical genetics, gastroenterology (for digestive system and liver problems), nephrology (for kidney problems), nutrition, cardiology (for heart problems), ophthalmology (for eye problems), liver transplantation, and child development. Treatment may include:[1][2][4][5][6][7][8]
  • Medication that increases bile flow (ursodeoxycholic acid) and that reduces the itching, such as cholestyramine, rifampin, and  naltrexone.
  • Biliary diversion procedures (partial internal biliary diversion and ileal exclusion) that interrupt the normal bile circulation between the intestines and liver resulting in the bile being eliminated and therefore lowering the blood bile levels. These procedures relieve symptoms of liver disease, such as itching, and improve the quality of life, but do not prevent the progression of liver disease.
  • Vitamin and special nutrition supplementation to support proper growth and development. Infants with Alagille syndrome are given a special formula that helps the small intestine absorb the fats. The diet usually is a high-calorie diet, calcium, and with vitamins A, D, E, and K, and sometimes zinc. Sometimes a  child may receive additional calories through a tiny tube that is passed through the nose into the stomach. If extra calories are needed for a long time, a doctor may place a tube, called a gastrostomy tube, directly into the stomach through a small opening made in the abdomen. Nutrition management may need to continue throughout a person's lifetime, but especially during childhood, with careful monitoring and balancing of nutrients, fat, calories, fat-soluble vitamins, calcium, and zinc. Each person with Alagille syndrome may have different dietary needs and the needs may change throughout their lifetime, so regular consultation with a nutrition specialists is recommended. 
  • Liver Transplantation to increase life span and improve liver function for those with end stage liver disease. Although there is some catch-up growth after a liver transplant in children with Alagille syndrome, it is not as much as seen in children with other liver diseases. 
  • Heart surgery or a catheter based procedure to correct a heart defect. Heart problems are treated the same as similar heart problems in children who do not have Alagille syndrome (standard medical care) although may be complicated if other organs are affected by the syndrome. 
  • Kidney surgery or treatment to correct any kidney abnormalities. Kidney problems are treated the same as kidney problems in children who do not have Alagille syndrome (standard medical care), although may be complicated if other organs are affected by the syndrome.
Heart problems may complicate liver transplantataion, especially, pulmonary artery stenosis with right ventricular pressure overload.  In these cases a procedure known as congenital heart transcatheter intervention may be done before the liver transplant.
Last updated: 10/20/2017
Some people with Alagille syndrome only have one or two minor findings associated with the syndrome, such as one of the harmless eye findings, butterfly vertebrae, innocent heart murmurs, or characteristic facial features. In fact, before genetic testing, a person with only these findings would not have been diagnosed with Alagille syndrome. People with only minor findings will not need treatment and can lead normal, productive lives unaffected by the complications of the syndrome. However, they do have a 50% chance of passing the genetic change causing Alagille syndrome onto each of their children, and it is not possible to predict how severely affected any of their children who inherit Alagille syndrome will be.[4][5]

For those with more serious symptoms of Alagille syndrome, the outlook depends on several factors, including the severity of liver damage and heart problems, and the early and continued correction of nutrition problems. Predicting who will experience improved bile flow and who will progress to end-stage liver failure is difficult since for some liver function improves over time. About 15% or more of the people with Alagille syndrome will eventually require a liver transplant.[1][4][5]

Children born with severe heart problems or who have serious liver problems may have a shortened lifespan.[1][9] However, due to improvements in liver and heart therapies, people are living longer, and those who respond well to the treatments and management of the syndrome, may lead normal, productive lives as adults. Deaths associated with Alagille syndrome are most often caused by liver failure, serious heart problems, or blood vessel abnormalities that cause bleeding in the brain or skull or strokes.[1][5]
Last updated: 10/20/2017

If you need medical advice, you can look for doctors or other healthcare professionals who have experience with this disease. You may find these specialists through advocacy organizations, clinical trials, or articles published in medical journals. You may also want to contact a university or tertiary medical center in your area, because these centers tend to see more complex cases and have the latest technology and treatments.

If you can’t find a specialist in your local area, try contacting national or international specialists. They may be able to refer you to someone they know through conferences or research efforts. Some specialists may be willing to consult with you or your local doctors over the phone or by email if you can't travel to them for care.

You can find more tips in our guide, How to Find a Disease Specialist. We also encourage you to explore the rest of this page to find resources that can help you find specialists.

Healthcare Resources

Related diseases are conditions that have similar signs and symptoms. A health care provider may consider these conditions in the table below when making a diagnosis. Please note that the table may not include all the possible conditions related to this disease.

Conditions with similar signs and symptoms from Orphanet
Differential diagnoses include biliary atresia, congenital hepatic fibrosis, cystic fibrosis, neonatal jaundice, polycystic kidney disease, progressive familial intrahepatic cholestasis, and tyrosinemia (see these terms).
Visit the Orphanet disease page for more information.

Research helps us better understand diseases and can lead to advances in diagnosis and treatment. This section provides resources to help you learn about medical research and ways to get involved.

Clinical Research Resources

  • ClinicalTrials.gov lists trials that are related to Alagille syndrome. Click on the link to go to ClinicalTrials.gov to read descriptions of these studies.

    Please note: Studies listed on the ClinicalTrials.gov website are listed for informational purposes only; being listed does not reflect an endorsement by GARD or the NIH. We strongly recommend that you talk with a trusted healthcare provider before choosing to participate in any clinical study.

Support and advocacy groups can help you connect with other patients and families, and they can provide valuable services. Many develop patient-centered information and are the driving force behind research for better treatments and possible cures. They can direct you to research, resources, and services. Many organizations also have experts who serve as medical advisors or provide lists of doctors/clinics. Visit the group’s website or contact them to learn about the services they offer. Inclusion on this list is not an endorsement by GARD.

Organizations Supporting this Disease

Organizations Providing General Support

These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

Where to Start

In-Depth Information

  • GeneReviews provides current, expert-authored, peer-reviewed, full-text articles describing the application of genetic testing to the diagnosis, management, and genetic counseling of patients with specific inherited conditions.
  • Medscape Reference provides information on this topic. You may need to register to view the medical textbook, but registration is free.
  • The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.
  • Online Mendelian Inheritance in Man (OMIM) is a catalog of human genes and genetic disorders. Each entry has a summary of related medical articles. It is meant for health care professionals and researchers. OMIM is maintained by Johns Hopkins University School of Medicine. 
  • Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.
  • PubMed is a searchable database of medical literature and lists journal articles that discuss Alagille syndrome. Click on the link to view a sample search on this topic.

Questions sent to GARD may be posted here if the information could be helpful to others. We remove all identifying information when posting a question to protect your privacy. If you do not want your question posted, please let us know.

  1. Alagille Syndrome. http://www.albireopharma.com/programs/a4250. January, 2019; http://digestive.niddk.nih.gov/ddiseases/pubs/alagille/.
  2. Alagille Syndrome. American Liver Foundation. http://www.liverfoundation.org/abouttheliver/info/alagille/.
  3. Alagille syndrome. Genetics Home Reference (GHR). 2014; http://ghr.nlm.nih.gov/condition=alagillesyndrome.
  4. Spinner NB, Hitchinson AL, Krantz ID, Kamath BM. Alagille Syndrome. GeneReviews. 2013; http://www.ncbi.nlm.nih.gov/books/NBK1273/.
  5. Alagille Syndrome. Children's Hospital of Pennsylvania (CHOP). http://www.chop.edu/conditions-diseases/alagille-syndrome.
  6. Berniczei-Royko A & cols. Medical and dental management of Alagille syndrome: A review. Med Sci Monit. 2014; 20:476-480. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3972053/pdf/medscimonit-20-476.pdf.
  7. Ramachandran P & cols. Outcome of partial internal biliary diversion for intractable pruritus in children with cholestatic liver disease. Pediatr Surg Int. 2014; 30(10):1045-9. http://www.ncbi.nlm.nih.gov/pubmed/25064227.
  8. Ben Ameur S, Chabchoub I, Telmoudi J & cols. Management of cholestatic pruritus in children with Alagille syndrome: Case report and literature review. Arch Pediatr. 2016; 23(12):1247-1250. https://www.ncbi.nlm.nih.gov/pubmed/28492167.
  9. Scheimann A. Alagille Syndrome. Medscape Reference. January 10, 2016; https://reference.medscape.com/article/926678-overview.
  10. Smithson S. Treatment of cardiovascular complications of Alagille syndrome in clinical optimization for liver transplantation. International Journal of Cardiology. 2014; 176(2):37-40. http://www.internationaljournalofcardiology.com/article/S0167-5273(14)00869-9/fulltext.