Alagille syndrome

This is part of Rare diseases.

Diagnosis: Alagille syndrome

Synonyms: Arteriohepatic dysplasia


Date of publication: 2014-10-08
Version: 3.0

ICD 10 code


The disease

Alagille syndrome is characterized by a specific combination of symptoms and signs. These include chronic liver disease which may cause jaundice, congenital cardiovascular disease, foetal abnormalities in the internal structure of the eye, a characteristic facial appearance, abnormalities of the vertebrae, other skeletal problems and impaired growth. Other organs, including the kidneys, the gastrointestinal tract and the nervous system, may also be affected. Some people may have impaired cognitive function. Both the nature and severity of symptoms vary greatly.

The syndrome was first described in 1969 by French paediatrician Daniel Alagille and his associates. The disease is also known as arteriohepatic dysplasia which refers to the abnormalities in the blood vessels and the liver.


Approximately two in every 100,000 children are born with Alagille syndrome, indicating that one or two children in Sweden are born annually with the condition. Approximately one or two individuals per 100,000 are affected, giving a total of around 100 individuals in Sweden with the syndrome. These figures are estimates, and may increase in the future with improved diagnostic procedures.


Most cases of the syndrome are caused by a mutation in a gene known as JAG1, found on chromosome 20 (20p12.2). JAG1 controls the formation of (codes for) a protein called JAG1. In less than one per cent of cases the disease is caused by a mutation in the NOTCH2 gene on chromosome 1 (11p12-11). NOTCH2 codes for a protein which belongs to a group known as notch receptors, which are embedded in cell membrane. They are activated by JAG1, which causes the part of the notch receptor located inside the cell to break loose, and be transported to the nucleus. In the nucleus various genes of importance for the growth and development of a large number of organs including the brain, liver, kidneys and skeleton, are activated. Many mutations in the JAG1 gene have been identified, but understanding the nature of the mutation does not indicate the type of symptoms which will develop. Neither is it possible to explain why the mutation causes such a wide variety of clinical symptoms.


The inheritance pattern of Alagille syndrome is autosomal dominant. This means that one of the parents has the disease, and so has one normal gene and one mutated gene. Sons and daughters of this parent have a 50 per cent risk of inheriting the disease. Children who do not inherit the mutated gene do not have the disease and do not pass it down.

Figure: Autosomal dominant inheritance

In approximately 20 per cent of people with the condition, the syndrome is caused by a new mutation. This means that the genetic mutation occurs in an individual for the first time and is not inherited from either parent. Consequently, parents with a child with a new mutation generally do not have an increased risk of having another child with the disorder. However, the new genetic mutation will be hereditary and an adult with this mutation risks passing on the mutated gene to his/her children.


The nature and severity of symptoms of Alagille syndrome vary greatly among individuals, including those from the same family. About 50 per cent of people with the disease show no symptoms, while for between 10 and 15 per cent, the syndrome leads to very serious liver, kidney or heart disease.

Prolonged jaundice or a heart murmur in a newborn can be early signs of disease and should lead to an examination of those organs likely to be affected by Alagille syndrome. Some of these infants may experience unexpected, sometimes life-threatening, haemorrhages as a result of vitamin K deficiency. This is the result of cholestasis, a condition where the bile, produced inside the liver cells, cannot reach the bowel. A few children have stunted growth at birth and can become very seriously ill during the neonatal period as several organs may be severely damaged. Sometimes the most severely affected infants do not survive the neonatal period.

The liver can be affected in a number of ways. The most common symptom is intrahepatic cholestasis. This means that a defect in the membranes of liver cells stops the excretion of the bile, which stays inside the liver cells and does not reach the intestine. The consequences are serious. Too little bile in the intestine leads to impaired absorption of fat and fat-soluble vitamins (A, D, E and K). This in turn can cause bleeding (sometimes life-threatening), rickets, impaired vision, neurological damage, and poor weight and growth gain. Too much bile in the tissues can cause severe itching, jaundice and thin and lifeless hair, while too much bile in the liver can lead to progressive liver disease and cirrhosis. It is extremely difficult to predict the outcome of this imbalance, which can range from slightly elevated levels of liver enzymes to such a severe form of the disease that a liver transplant is necessary. There is also an increased risk that those with Alagille syndrome will develop liver cancer before the age of 40.

Most people with the syndrome have some kind of congenital heart defect or a slight anatomical abnormality in the cardiovascular system. Pulmonary stenosis, an abnormal narrowing of the major artery leading blood to the lungs, is the most common. This narrowing can cause symptoms ranging from a harmless heart murmur to a disabling condition, which may be both life-threatening and inoperable. Other cardiovascular problems can occur, probably caused by abnormalities in the composition of tissue in the blood vessel walls. This may result in a cardiovascular condition known as moyamoya, or unexpected and sometimes life-threatening complications following major operations, for example after a liver transplant. Separate information on moyamoya is available in the Rare Disease Database of the Swedish Board of Health and Welfare.

In the eye, the back of the cornea is often thickened (posterior embryotoxon), but vision is rarely affected. However, where pigment changes and retinal degeneration occur, the result may be impaired vision.

Alagille syndrome is also associated with characteristic facial features, including a broad, protruding forehead, thin hair, deeply-set eyes and a slightly underdeveloped jaw, which causes an underbite.

Skeletal abnormalities in people with the disease are not the result of vitamin D deficiency or kidney disease. In X-rays it is often possible to see individual or multiple vertebrae which are not fully developed. (These may be called “butterfly vertebrae” as their shape resembles a butterfly’s wings.) This abnormality does not lead to symptoms in childhood but in the long term can cause back problems when the individual reaches adulthood as these vertebrae are less strong than normal. Other abnormalities in bone structure may be seen in X-rays but do not lead to clinical symptoms. Some children with Alagille syndrome have impaired growth, but this is not related to nutritional shortcomings and is not responsive to growth hormone. There is also a small group of children with the disease who develop a very severe form of osteopenia/osteoporosis which may lead to physical disability.

The kidneys can also be affected in various ways and to varying degrees. This may be seen first as an over-sensitivity to medication, but can sometimes lead to slowly progressive kidney disease or renal failure.

Neurological complications can arise as a result of impaired levels of blood fats and vitamin E, if the disease is not treated. Most people with Alagille syndrome have normal cognitive function, although a few may have an intellectual disability. The severity of symptoms varies greatly.

Changes in the individual’s liver, kidneys and skeleton, as well as nutritional deficiencies, can be monitored in laboratory tests. Approximately half of those with Alagille syndrome, above all young children, have moderate to extreme elevation of blood lipid levels. This can cause local accumulations of cholesterol in the skin (xanthoma). The cause of these elevated levels of blood fats is unknown, but indications are that the high levels do not lead to a significantly increased risk of developing cardiovascular disease early in life.


The diagnosis Alagille syndrome is made mainly on the basis of clinical observation, and can sometimes be very difficult to confirm. In infants, prolonged jaundice, a heart murmur and the presence of certain characteristic facial features may be indications of the disease. A thorough examination of the liver and heart should be carried out. The results will determine prognosis and future treatment.

It is usually possible to confirm the diagnosis using DNA-based analysis. At the time of diagnosis it is important that the family is offered genetic counselling. Carrier and prenatal diagnosis, as well as pre-implantation genetic diagnosis (PGD) in association with IVF (in vitro fertilization), are available to families where the mutation is known.


There is no specific treatment which will cure the underlying cause of the disease. All children with Alagille syndrome should undergo thorough investigations of the liver, heart, kidneys, eyes, skeleton and central nervous system. Regular and frequent check-ups to monitor the progress of the disease make it possible to treat each symptom as it arises.

A few children with Alagille syndrome are seriously ill at birth, suffering from impaired growth and organ failure, and require neonatal care. In some cases these infants do not survive this period.

To counteract the effect of the disease on the liver and reduce itching, treatment usually involves attempting to stimulate the flow of bile. The child’s food intake must be rigorously monitored. Approximately half the children with the syndrome require an intensive nutritional regime which includes supplements of fat-soluble vitamins. It is important that the family has early contact with a dietician with knowledge of the disease. To monitor the development of the disease regular check-ups, ultrasound examinations and liver biopsies are required. These procedures make it possible to identify children who may be future candidates for liver transplants in good time.

In Alagille syndrome, itching is similar to that associated with other forms of liver disease, although the disease can affect both liver and kidneys. The itching often starts at around the age of five or six months and becomes more severe as the child gets older. This can lead to disability in the form of concentration problems and fatigue, which can impact on school performance in childhood, and later on working capacity. Commonly used symptomatic treatments such as ointments, cortisone and anti-allergic treatments, have no effect. Other forms of treatment including ultraviolet light treatment, purification of the blood by use of a filter or ultraviolet light, acupuncture, and electrical stimulation of the skin have all been tested, with varying degrees of success. If kidney function is good, itching can often be treated successfully with medication, including those which stimulate bile flow. For those few cases where both liver and kidney function is severely impaired, it is often difficult to treat the itching. For those individuals, a liver and/or kidney transplant may be considered.

It is important that kidney function is monitored regularly.

The child’s heart should be examined by a paediatric cardiologist. Regular monitoring is usually necessary and heart surgery is sometimes required.

The eyes should also be examined. Aids to vision may be required.

A few children with Alagille syndrome have intellectual disabilities and it is important to identify them as early as possible. The affected individual’s family should be offered help from a habilitation team. This team includes professionals with special expertise in how disability affects everyday life, health and development. Support and treatment involves medical, educational, psychological, social and technical aspects, and also includes visual habilitation. Information is also offered about support available through Swedish public authorities. Habilitation should focus on the child’s particular needs. Measures should occur in collaboration with the family and other individuals close to the child.

Having a child with a progressive disease may be a great strain for everyone involved. Psychological and social support is important, both for the person affected and for the family. It is important to provide those in contact with the child, including personnel at day care and school, with clear information to increase understanding of the condition.

Adults with Alagille syndrome

Adults severely affected by the disease have often had contact with the medical services throughout childhood. In adulthood, regular monitoring of the progression of the disease should continue as previously. Psychological and social support continue to be important for individuals with the syndrome. People with an intellectual disability require continued, individually-designed support from adult habilitation services. Care and support in daily life can be provided in specially-adapted accommodation.

Those who receive the diagnosis as adults (usually at the same time that one of their children is diagnosed) often have no, or very mild, symptoms. The diagnosis is made if it is possible to show that the adult has the same mutation which has caused the disease in the child, or by observing particular symptoms and signs, such as elevated levels of blood fats. After the first examination only preventive monitoring is subsequently required. This involves the measurement of blood fat levels and regular ultrasound examinations of the liver.

It is probable that itching during pregnancy is more common in women with Alagille syndrome than in other women. The condition can usually be treated with medication.

Practical advice


National and regional resources in Sweden

Department of Paediatric Gastroenterology, Hepatology and Nutrition, Astrid Lindgren Children’s Hospital, Solna, SE-171 76 Stockholm, Sweden. Tel: +46 8 517 700 00.

Department of Surgical Transplantation, Karolinska University Hospital, Huddinge, SE-141 86 Stockholm, Sweden. Tel: +46 8 585 800 00.

The Queen Silvia Children’s Hospital, SE-416 85 Gothenburg, Sweden. Tel: +46 31 343 40 00.

Resource personnel

Professor Bo-Göran Ericzon, Department of Surgical Transplantation , Karolinska University Hospital, Huddinge, SE-141 86 Stockholm, Sweden. Tel: +46 8 585 800 00, email: bo-goran.ericzon@karolinska.se.

Associate Professor Björn Fischler, Astrid Lindgren Children’s Hospital/Huddinge, SE-141 86 Stockholm, Sweden. Tel: +46 8 585 00 000, email: bjorn.fischler@karolinska.se.

Specialist physician Audur H Gudjónsdóttir, The Queen Silvia Children’s Hospital, SE-416 85 Gothenburg, Sweden. Tel: +46 31 343 10 00, email: audur.gudjonsdottir@vgregion.se.

Professor Antal Németh, Astrid Lindgrens Children’s Hospital /Huddinge, SE-141 86 Stockholm, Sweden. Tel: +46 8 585 814 68, email: antal.nemeth@ki.se.

Courses, exchanges of experience, recreation


Organizations for the disabled/patient associations etc.

RFL, Swedish Association for People with Liver Disease. Email: kansli@rfl-lever.se, http://rfl-lever.blogspot.se.

FUB, The Swedish National Association for Children, Young People and Adults with Intellectual Disabilities, Industrivägen 7 (visitors address), Box 1181, 171 23 Solna, Sweden. Tel: +46 8 508 866 00, fax: +46 8 508 866 66, email: fub@fub.se, www.fub.se.

SRF, The Swedish Association of the Visually Impaired, Sandsborgsvägen 52, SE-122 88 Enskede, Sweden. Tel: +46 8 39 90 00, fax: +46 8 39 93 22, email: info@srf.nu, www.srf.nu.

Courses, exchanges of experience for personnel


Research and development

Swedish research on Alagille syndrome and other progressive liver diseases in children is carried out at the Department of Paediatrics and the Department of Transplant Surgery, Karolinska University Hospital, Huddinge, in Stockholm.

Information material

Short summaries of all the database texts are available as leaflets, in Swedish only. They can be printed out or ordered by selecting the Swedish version, and then clicking on the leaflet icon which will appear under, “Mer hos oss” in the column on the right-hand side.


Alagille D, Estrada A, Hadchouel M, Gautier M, Odièvre M, Dommergues JP. Syndromic paucity of interlobular bile ducts (Alagille syndrome or arteriohepatic dysplasia): review of 80 cases. J Pediatr 1987; 110: 195-200.

Alagille D, Habib EC, Thomassin N. L’atrésie des voies biliaires intrahépatiques avec voies biliaires extrahépatiques perméables chez l’enfant. A propos de 25 observations. Paris: Editions Médicales Flammarion 1969; 301-318.

Arvay JL, Zemel BS, Gallagher PR, Rovner AJ, Mulberg AE, Stallings VA et al. Body composition of children aged 1 to 12 years with biliary artesia or Alagille syndrome. J Pediatr Gastroenterol Nutr 2005; 40: 146-150.

Cardona J, Houssin D, Gauthier F, Devictor D, Losay J, Hadchouel M et al. Liver transplantation in children with Alagille syndrome – a study of twelve cases. Transplantation 1995; 60: 339-342.

Colliton RP, Bason L, Lu FM, Piccoli DA, Krantz ID, Spinner NB. Mutation analysis of Jagged 1 (JAG1) in Alagille syndrome patients. Hum Mutat 2001; 17: 151-152.

Deutsch GH, Sokol RJ, Stathos TH, Knisely AS. Proliferation to paucity: evolution of bile duct abnormalities in a case of Alagille syndrome. Pediatr Developm Pathol 2001; 4: 559-563.

Elmslie FV, Vivian AJ, Gardiner H, Hall C, Mowat AP, Winter RM. Alagille syndrome: family studies. J Med Genet 1995; 32: 264-268.

Emerick KM, Krantz ID, Kamath BM, Darling C, Burrowes DM, Spinner NB et al. Intracranial vascular abnormalities in patients with Alagille syndrome. J Pediatr Gastroenterol Nutr 2005; 41: 99-107.

Englert C, Grabhorn E, Burdelski M, Ganschow R. Liver transplantation in children with Alagille syndrome: indications and outcome. Pediatric Transplant 2006; 10: 154-158.

Fiza U-M, Martinez Aria A. Cell and molecular biology of Notch. J Endocrinol 2007; 194: 459-474.

Giannakudis J, Ropke A, Kujat A, Krajewska-Walasek M, Hughes H, Fryns JP et al. Parental mosaicism of JAG1 mutations in families with Alagille syndrome. Europ J Hum Genet 2001; 9: 209-216.

Haberal M, Arda IS, Karakayali H, Emiroglu R, Bilgin N, Arslan G et al. Successful heterotopic segmental liver transplantation from a live donor to a patient with Alagille syndrome. J Pediatr Surg 2001; 36: 667-671.

Hingorani M, Nischal KK, Davies A, Bentley C, Vivian A, Baker AJ et al. Ocular abnormalities in Alagille syndrome. Ophthalmology 1999; 106: 330-337.

Kamath BM, Bason L, Piccoli DA, Krantz ID, Piccoli DA, Spinner NB. Alagille syndrome. J Med Genet 1997; 34: 152-157.

Kamath BM, Bason L, Piccoli DA, Krantz ID, Spinner NB. Consequences of JAG1 mutations. J Med Genet 2003; 40: 891-895.

Kasahara M, Kiuchi T, Inomata Y, Uryuhara K, Sakamoto S, Ito T et al. Living-related liver transplantation for Alagille syndrome. Transplantation 2003; 75: 2147-2150.

Krantz ID, Piccoli DA, Spinner NB. Alagille syndrome. J Med Genet 1997; 34: 152-157.

Li L, Krantz ID, Deng Y, Genin A, Banta AB, Collins CC et al. Alagille syndrome is caused by mutations in human Jagged 1, which encodes a ligand for Notch 1. Nat Genet 1997; 16: 243-250.

Lykavieris P, Crosnier C, Trichet C, Meunier-Rotival M, Hadchouel M. Bleeding tendency in children with Alagille syndrome. J Pediatric Gastroenterol Nutr 2003; 36: 509.

Lykavieris P, Hadchouel M, Chardot C, Bernard O. Outcome of liver disease in children with Alagille syndrome: a study of 163 patients. Gut 2001; 49: 431-435.

Mattei P, von Allmen D, Piccoli D, Rand E. Relief of intractable pruritus in Alagille syndrome by partial external biliary diversion. J Pediatr Surg 2006; 41: 104-107.

Narula P, Gifford J, Steggall MA, Lloyd C, Van Mourik ID, McKiernan PJ et al. Visual loss and idiopathic intracranial hypertension in children with Alagille syndrome. J Pediatr Gastroenterol Nutr 2006; 43: 348-352.

Png K, Veyckemans F, De Kock M, Carlier M, Sluymans T, Otte JB et al. Hemodynamic changes in patients with Alagille’s syndrome during orthoptic liver transplantation. Anesth Analg 1999; 89: 1137-1142.

Quiros-Tejeira RE, Ament ME, Heyman MB, Martin MG, Rosenthal P, Gornbein JA et al. Does liver transplantation affect growth pattern in Alagille syndrome? Liver Transpl 2000; 6: 582-587.

Silberbach M, Lashley D, Reller MD, Kinn WF, Terry A, Sunderland CO. Arteriohepatic dysplasia and cardiovascular malformations. Am Heart J 1994; 127: 695-699.

Tear Fahnehjelm K, Fischler B, Martin L, Németh A. Occurrence and pattern of ocular disease in children with cholestatic disorders. Acta Ophtalmol, In press.

Warthen DM, Moore EC, Kamath BM, Morrissette JJ, Sanchez P, Piccoli DA et al. Jagged1 (JAG1) mutations in Alagille syndrome: increasing the mutation detection rate. Hum Mutat 2006; 27: 436-443.

Wolfish NM, Shanon A. Nephropathy in arteriohepatic dysplasia (Alagille syndrome). Child Nephrol Urol 1988; 9: 169-172.

Yuan ZR, Okinawa M, Nagata I, Tazawa Y, Ito M, Kawarazaki H et al. The DSL domain in mutant Jag1 ligand is essential for the severity of the liver defect in Alagille syndrome. Clin Genet 2001; 59: 330-337.

Zanotti S, Canalis E. Notch signaling i skeletal helath and disease. Eur J Endocrinol 2013; 168: 95-103.

Database references

OMIM (Online Mendelian Inheritance in Man)
Search: alagille syndrome

GeneReviews (University of Washington)
www.genetests.org (select GeneReviews, then Titles)
Search: alagille syndrome

Document information

The Swedish Information Centre for Rare Diseases produced and edited this information material.

The medical expert Professor Karl-Henrik Gustavson, Uppsala University Hospital, wrote the draft of this information material.

The material has been revised by Professor Antal Németh, Astrid Lindgren Children’s Hospital, Stockholm, Sweden.

The relevant organizations for the disabled/patient associations have been given the opportunity to comment on the content of the text.

An expert group on rare diseases, affiliated with the University of Gothenburg, approved the material prior to publication.

Date of publication: 2014-10-08
Version: 3.0
Publication date of the Swedish version: 2014-01-29

For enquiries contact The Swedish Information Centre for Rare Diseases, The Sahlgrenska Academy at the University of Gothenburg, Box 422, SE-405 30 Gothenburg, Sweden. Tel: +46 31 786 55 90, email: ovanligadiagnoser@gu.se.


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