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Disease Profile

Alagille syndrome

Prevalence
Prevalence estimates on Rare Medical Network websites are calculated based on data available from numerous sources, including US and European government statistics, the NIH, Orphanet, and published epidemiologic studies. Rare disease population data is recognized to be highly variable, and based on a wide variety of source data and methodologies, so the prevalence data on this site should be assumed to be estimated and cannot be considered to be absolutely correct.

Unknown

Age of onset

All ages

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ICD-10

Q44.7

Inheritance

Autosomal dominant A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease

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Autosomal recessive Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype

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X-linked
dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

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X-linked
recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder

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Mitochondrial or multigenic Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy.

Multigenic or multifactor Inheritance involving many factors, of which at least one is genetic but none is of overwhelming importance, as in the causation of a disease by multiple genetic and environmental factors.

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Not applicable

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Other names (AKA)

Hepatic ductular hypoplasia; Watson Alagille syndrome; Alagille-Watson syndrome;

Categories

Congenital and Genetic Diseases

Summary

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]

Symptoms

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.

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.

Treatment

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.

Medical Terms Other Names
Learn More:
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
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.

Organizations

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

      Learn more

      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.

          References

          1. Alagille Syndrome. https://www.albireopharma.com/programs/a4250. January, 2019; https://digestive.niddk.nih.gov/ddiseases/pubs/alagille/.
          2. Alagille Syndrome. American Liver Foundation. https://www.liverfoundation.org/abouttheliver/info/alagille/.
          3. Alagille syndrome. Genetics Home Reference (GHR). 2014; https://ghr.nlm.nih.gov/condition=alagillesyndrome.
          4. Spinner NB, Hitchinson AL, Krantz ID, Kamath BM. Alagille Syndrome. GeneReviews. 2013; https://www.ncbi.nlm.nih.gov/books/NBK1273/.
          5. Alagille Syndrome. Children's Hospital of Pennsylvania (CHOP). https://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. https://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. https://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. https://www.internationaljournalofcardiology.com/article/S0167-5273(14)00869-9/fulltext.

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