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Genetics Home Reference: your guide to understanding genetic conditions
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Alagille syndrome

Reviewed April 2010

What is Alagille syndrome?

Alagille syndrome is a genetic disorder that can affect the liver, heart, and other parts of the body.

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 (bile duct paucity). As a result, bile builds up in the liver and causes scarring that prevents the liver from working properly to eliminate wastes from the bloodstream. Signs and symptoms arising from liver damage in Alagille syndrome may include a yellowish tinge in the skin and the whites of the eyes (jaundice), itchy skin, and deposits of cholesterol in the skin (xanthomas).

Alagille syndrome is also associated with several heart problems, including impaired blood flow from the heart into the lungs (pulmonic stenosis). Pulmonic stenosis may occur along with a hole between the two lower chambers of the heart (ventricular septal defect) and other heart abnormalities. This combination of heart defects is called tetralogy of Fallot.

People with Alagille syndrome may have distinctive facial features including a broad, prominent forehead; deep-set eyes; and a small, pointed chin. The disorder may also affect the blood vessels within the brain and spinal cord (central nervous system) and the kidneys. Affected individuals may have an unusual butterfly shape of the bones of the spinal column (vertebrae) that can be seen in an x-ray.

Problems associated with Alagille syndrome generally become evident in infancy or early childhood. The severity of the disorder varies among affected individuals, even within the same family. Symptoms range from so mild as to go unnoticed to severe heart and/or liver disease requiring transplantation.

Some people with Alagille syndrome may have isolated signs of the disorder, such as a heart defect like tetralogy of Fallot, or a characteristic facial appearance. These individuals do not have liver disease or other features typical of the disorder.

How common is Alagille syndrome?

The estimated prevalence of Alagille syndrome is 1 in 70,000 newborns. This figure is based on diagnoses of liver disease in infants, and may be an underestimation because some people with Alagille syndrome do not develop liver disease during infancy.

What are the genetic changes related to Alagille syndrome?

In more than 90 percent of cases, mutations in the JAG1 gene cause Alagille syndrome. Another 7 percent of individuals with Alagille syndrome have small deletions of genetic material on chromosome 20 that include the JAG1 gene. A few people with Alagille syndrome have mutations in a different gene, called NOTCH2. The JAG1 and NOTCH2 genes provide instructions for making proteins that fit together to trigger interactions called Notch signaling between neighboring cells during embryonic development. This signaling influences how the cells are used to build body structures in the developing embryo. Changes in either the JAG1 gene or NOTCH2 gene probably disrupt the Notch signaling pathway. As a result, errors may occur during development, especially affecting the bile ducts, heart, spinal column, and certain facial features.

Related Chromosome(s)

Changes involving this chromosome are associated with Alagille syndrome.

  • chromosome 20

Related Gene(s)

Changes in these genes are associated with Alagille syndrome.

  • JAG1
  • NOTCH2

Can Alagille syndrome be inherited?

This condition is inherited in an autosomal dominant pattern, which means one copy of the altered or deleted gene in each cell is sufficient to cause the disorder.

In approximately 30 to 50 percent of cases, an affected person inherits the mutation or deletion from one affected parent. Other cases result from new mutations in the gene or new deletions of genetic material on chromosome 20 that occur as random events during the formation of reproductive cells (eggs or sperm) or in early fetal development. These cases occur in people with no history of the disorder in their family.

Where can I find information about diagnosis or management of Alagille syndrome?

These resources address the diagnosis or management of Alagille syndrome and may include treatment providers.

  • Boston Children's Hospital (http://www.childrenshospital.org/health-topics/conditions/a/alagille-syndrome)
  • Children's Hospital of Pittsburgh (http://www.chp.edu/CHP/Alagille)
  • Childrens Hospital of Philadelphia (http://www.chop.edu/service/alagille-syndrome-clinical-care-program/symptoms-treatment/)
  • Gene Review: Alagille Syndrome (http://www.ncbi.nlm.nih.gov/books/NBK1273/)
  • Genetic Testing Registry: Alagille syndrome 1 (http://www.ncbi.nlm.nih.gov/gtr/conditions/C1956125)
  • Genetic Testing Registry: Arteriohepatic dysplasia (http://www.ncbi.nlm.nih.gov/gtr/conditions/C0085280)
  • MedlinePlus Encyclopedia: Tetralogy of Fallot (http://www.nlm.nih.gov/medlineplus/ency/article/001567.htm)

You might also find information on the diagnosis or management of Alagille syndrome in Educational resources (http://www.ghr.nlm.nih.gov/condition/alagille-syndrome/show/Educational+resources) and Patient support (http://www.ghr.nlm.nih.gov/condition/alagille-syndrome/show/Patient+support).

General information about the diagnosis (http://ghr.nlm.nih.gov/handbook/consult/diagnosis) and management (http://ghr.nlm.nih.gov/handbook/consult/treatment) of genetic conditions is available in the Handbook. Read more about genetic testing (http://ghr.nlm.nih.gov/handbook/testing), particularly the difference between clinical tests and research tests (http://ghr.nlm.nih.gov/handbook/testing/researchtesting).

To locate a healthcare provider, see How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.

Where can I find additional information about Alagille syndrome?

You may find the following resources about Alagille syndrome helpful. These materials are written for the general public.

You may also be interested in these resources, which are designed for healthcare professionals and researchers.

What other names do people use for Alagille syndrome?

  • Alagille's syndrome
  • Alagille-Watson Syndrome
  • arteriohepatic dysplasia (AHD)
  • cardiovertebral syndrome
  • cholestasis with peripheral pulmonary stenosis
  • hepatic ductular hypoplasia
  • hepatofacioneurocardiovertebral syndrome
  • paucity of interlobular bile ducts
  • Watson-Miller syndrome

For more information about naming genetic conditions, see the Genetics Home Reference Condition Naming Guidelines (http://ghr.nlm.nih.gov/ConditionNameGuide) and How are genetic conditions and genes named? (http://ghr.nlm.nih.gov/handbook/mutationsanddisorders/naming) in the Handbook.

What if I still have specific questions about Alagille syndrome?

Ask the Genetic and Rare Diseases Information Center (http://rarediseases.info.nih.gov/GARD/).

What glossary definitions help with understanding Alagille syndrome?

aorta ; autosomal ; autosomal dominant ; bile ; bile duct ; cell ; central nervous system ; cholesterol ; chromosome ; deletion ; duct ; dysplasia ; embryo ; embryonic ; gallbladder ; gene ; hepatic ; hypoplasia ; inherited ; intestine ; jaundice ; mutation ; neonatal ; nervous system ; peripheral ; prevalence ; pulmonary ; pulmonary stenosis ; pulmonic stenosis ; reproductive cells ; septal defect ; sperm ; stenosis ; syndrome ; tetralogy of Fallot

You may find definitions for these and many other terms in the Genetics Home Reference Glossary (http://www.ghr.nlm.nih.gov/glossary).

References

  • Boyer-Di Ponio J, Wright-Crosnier C, Groyer-Picard MT, Driancourt C, Beau I, Hadchouel M, Meunier-Rotival M. Biological function of mutant forms of JAGGED1 proteins in Alagille syndrome: inhibitory effect on Notch signaling. Hum Mol Genet. 2007 Nov 15;16(22):2683-92. Epub 2007 Aug 24. (http://www.ncbi.nlm.nih.gov/pubmed/17720887?dopt=Abstract)
  • Gene Review: Alagille Syndrome (http://www.ncbi.nlm.nih.gov/books/NBK1273/)
  • Kamath BM, Bason L, Piccoli DA, Krantz ID, Spinner NB. Consequences of JAG1 mutations. J Med Genet. 2003 Dec;40(12):891-5. (http://www.ncbi.nlm.nih.gov/pubmed/14684686?dopt=Abstract)
  • Kim BJ, Fulton AB. The genetics and ocular findings of Alagille syndrome. Semin Ophthalmol. 2007 Oct-Dec;22(4):205-10. Review. (http://www.ncbi.nlm.nih.gov/pubmed/18097983?dopt=Abstract)
  • McDaniell R, Warthen DM, Sanchez-Lara PA, Pai A, Krantz ID, Piccoli DA, Spinner NB. NOTCH2 mutations cause Alagille syndrome, a heterogeneous disorder of the notch signaling pathway. Am J Hum Genet. 2006 Jul;79(1):169-73. Epub 2006 May 10. (http://www.ncbi.nlm.nih.gov/pubmed/16773578?dopt=Abstract)
  • OMIM: ALAGILLE SYNDROME 1 (http://omim.org/entry/118450)
  • Piccoli DA, Spinner NB. Alagille syndrome and the Jagged1 gene. Semin Liver Dis. 2001 Nov;21(4):525-34. Review. (http://www.ncbi.nlm.nih.gov/pubmed/11745040?dopt=Abstract)
  • Spinner NB, Colliton RP, Crosnier C, Krantz ID, Hadchouel M, Meunier-Rotival M. Jagged1 mutations in alagille syndrome. Hum Mutat. 2001;17(1):18-33. Review. (http://www.ncbi.nlm.nih.gov/pubmed/11139239?dopt=Abstract)
  • Suskind DL, Murray KF. Increasing the mutation rate for Jagged1 mutations in patients with Alagille syndrome. Hepatology. 2007 Aug;46(2):598-9. (http://www.ncbi.nlm.nih.gov/pubmed/17661408?dopt=Abstract)
  • Warthen DM, Moore EC, Kamath BM, Morrissette JJ, Sanchez-Lara PA, Piccoli DA, Krantz ID, Spinner NB. Jagged1 (JAG1) mutations in Alagille syndrome: increasing the mutation detection rate. Hum Mutat. 2006 May;27(5):436-43. Erratum in: Hum Mutat. 2013 Feb;34(2):408. Sanchez, P [corrected to Sanchez-Lara, P A]. (http://www.ncbi.nlm.nih.gov/pubmed/16575836?dopt=Abstract)

 

The resources on this site should not be used as a substitute for professional medical care or advice. Users seeking information about a personal genetic disease, syndrome, or condition should consult with a qualified healthcare professional. See How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.

 
Reviewed: April 2010
Published: July 28, 2014