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OVERVIEW2018-07-10T15:22:08+00:00

OVERVIEW


This report on Alagille Syndrome has been developed by Henry C. Lin MD, in conjunction with the National Organization for Rare Disorders (NORD) for NORD’s copyrighted Rare Disease Database, an educational resource for students, medical professionals and the public. ALGSA is a member of NORD.

Synonyms of Alagille Syndrome
Alagille-Watson syndrome
arteriohepatic dysplasia
cholestasis with peripheral pulmonary stenosis
syndromic bile duct paucity

General Discussion
Alagille syndrome (OMIM #118450) is a rare genetic disorder that can affect multiple organ systems of the body including the liver, heart, skeleton, eyes and kidneys. The specific symptoms and severity of Alagille syndrome can vary greatly from one person to another, even within the same family. Some individuals may have mild forms of the disorder while others may have more serious forms. Common symptoms, which often develop during the first three months of life, include blockage of the flow of bile from the liver (cholestasis), yellowing of the skin and mucous membranes (jaundice), poor weight gain and growth, severe itching (pruritis) and pale, loose stools. Additional symptoms include heart murmurs, congenital heart defects, vertebral (back bone) differences, thickening of the ring that normally lines the cornea in the eye (posterior embryotoxon) and distinctive facial features. Most people with Alagille syndrome have mutations in one copy of the JAG1 gene. A small percentage (less than 1 percent) of patients have mutations of the NOTCH2 gene. These mutations are inherited as autosomal dominant traits, however in about half of cases the mutation occurs as a new change (“de novo”) in the individual and was not inherited from a parent. The current estimated incidence of ALGS is between 1:30,000 and 1:45,000 with no difference in gender.

Alagille syndrome (OMIM #118450) is a rare genetic disorder that can affect multiple organ systems of the body including the liver, heart, skeleton, eyes and kidneys. The specific symptoms and severity of Alagille syndrome can vary greatly from one person to another, even within the same family. Some individuals may have mild forms of the disorder while others may have more serious forms. Common symptoms, which often develop during the first three months of life, include blockage of the flow of bile from the liver (cholestasis), yellowing of the skin and mucous membranes (jaundice), poor weight gain and growth, severe itching (pruritis) and pale, loose stools. Additional symptoms include heart murmurs, congenital heart defects, vertebral (back bone) differences, thickening of the ring that normally lines the cornea in the eye (posterior embryotoxon) and distinctive facial features. Most people with Alagille syndrome have mutations in one copy of the JAG1 gene. A small percentage (less than 1 percent) of patients have mutations of the NOTCH2 gene. These mutations are inherited as autosomal dominant traits, however in about half of cases the mutation occurs as a new change (“de novo”) in the individual and was not inherited from a parent. The current estimated incidence of ALGS is between 1:30,000 and 1:45,000 with no difference in gender.

The symptoms and severity of Alagille syndrome can vary greatly from one person to another, even among members of the same family. Some individuals may have a mild form of the disorder that can virtually go unnoticed; other individuals may have a serious form of the disorder that can potentially cause life-threatening complications. It is important to note that affected individuals may not have all of the symptoms discussed below. Affected individuals should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.

Alagille syndrome can be associated with abnormalities of the liver, heart, eyes, skeleton, kidneys and other organ systems of the body. A main finding of Alagille syndrome is liver disease that often becomes apparent within the first three months of life. However, in individuals with mild liver involvement, a diagnosis may not be made into later in life. Liver disease in Alagille syndrome, if present, may range in severity from jaundice or mild cholestasis to severe, progressive liver disease that can potentially result in liver failure.

Approximately 90 percent of individuals with Alagille syndrome have a reduced number of bile ducts (bile duct paucity) within the liver. Bile ducts are small tube-like structures that carry bile from the liver to the small intestines. The formation of bile is one of the functions of the liver. Bile is a fluid that contains water, certain minerals that carry an electric charge (electrolytes), and other materials including bile salts, phospholipids, cholesterol, and an orange-yellow pigment (bilirubin) that is a byproduct of the natural breakdown of the hemoglobin of red blood cells. Bile flow accomplishes two important tasks within the body: it aids in digestion and absorption of dietary fats, vitamins, and other nutrients and helps eliminate excess cholesterol, bilirubin, waste, and toxins from the body. Therefore, a problem with bile flow often results in malabsorption of vital nutrients and the accumulation of toxic materials in the body.

Because of the reduced number of bile ducts, individuals with Alagille syndrome can develop jaundice and cholestasis usually during the first four months of life. Cholestasis refers to reduced or obstructed flow of bile from the liver. Cholestasis can cause yellowing of the skin and whites of the eyes (jaundice), itching (pruritus) that may be intense, pale-colored stools, dark urine, fatty sores or bumps (xanthomas) just under the surface of the skin, and an abnormally enlarged liver (hepatomegaly) and/or enlarged spleen (splenomegaly). Because the body cannot properly absorb fats and fat-soluble vitamins (vitamins A, D, E, and K), affected children may also experience growth deficiencies and failure to thrive. Malabsorption of vital nutrients can also lead to rickets, a condition marked by softened, weakened bones (vitamin D deficiency), vision problems (vitamin A deficiency), poor coordination and developmental delays (vitamin E deficiency) and blood clotting problems (vitamin K deficiency).

In approximately 15 percent of patients, progressive liver disease results in scarring of the liver (cirrhosis) and liver failure. There is no way to tell which children are at risk for serious, progressive liver disease in Alagille syndrome.

Many individuals with Alagille syndrome have heart (cardiac) abnormalities that can range from benign heart murmurs to serious structural defects. A heart murmur is an extra sound that is heard during a heartbeat. Heart murmurs in children with Alagille syndrome are usually caused by narrowing of the blood vessels of the lungs (pulmonary artery stenosis). Some children with Alagille syndrome may have complex heart defects, the most common of which is tetralogy of Fallot. Tetralogy of Fallot is a rare form of cyanotic heart disease. Cyanosis is abnormal bluish discoloration of the skin and mucous membranes that occurs due to low levels of circulating oxygen in the blood. Tetralogy of Fallot consists of a combination of four different heart defects: ventricular septal defect, obstructed outflow of blood from the right ventricle to the lungs due to an abnormal narrowing of the opening between the pulmonary artery and the right ventricle of the heart (pulmonary stenosis), displaced aorta that causes blood to flow into the aorta from both the right and left ventricles, and abnormal enlargement of the right ventricle.

Additional heart defects that can occur in Alagille syndrome include ventricular septal defects, atrial septal defects, patent ductus arteriosus, and coarctation of the aorta. Some studies have shown that in rare cases there is an association with WolffParkinson-White syndrome, a condition characterized by electrical disturbances in the heart. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)

Some individuals with Alagille syndrome may have eye (ocular) abnormalities, especially posterior embryotoxon, a condition marked by thickening of the ring that normally lines the cornea in the eye. The cornea is the thin, transparent membrane that covers the eyeballs. In most cases, posterior embryotoxon is a benign finding that primarily helps to establish a clinical diagnosis and vision is usually unaffected, although mild decreases in the clarity of vision may occur. Less commonly, other eye abnormalities may occur such as Axenfeld anomaly, a condition in which strands of the iris are abnormally attached to the cornea, or progressive degeneration of the retina (pigmentary retinopathy). The retina is the thin layers of nerve cells that lines that inner surface of the back of the eyes and senses light and converts it to nerve signals, which are then relayed to the brain through the optic nerve.

Individuals with Alagille syndrome usually have distinctive facial features including deeply-set and widely spaced (hypertelorism) eyes, a pointed chin, broad forehead, and low-set, malformed eyes. In older individuals and adults, the chin may appear larger and more prominent (prognathia).  Skeletal abnormalities may occur in some individuals with Alagille syndrome including butterfly vertebrae, a condition in which certain bones of the spinal column are irregularly-shaped. This condition is often noted on an x-ray, but usually does not cause any symptoms or problems (asymptomatic).

Additional symptoms may occur in some individuals with Alagille syndrome including kidney (renal) abnormalities, pancreatic insufficiency, vascular anomalies, mild developmental delays and cognitive impairment. Kidney abnormalities may be more prevalent in individuals with Alagille syndrome caused by mutations in the NOTCH2 gene and include abnormally small kidneys, the presence of cysts on the kidneys and decreased or impaired kidney function. The pancreas is a small organ located behind the stomach that secretes enzymes that travel to the intestines and aid in digestion. The pancreas also secretes other hormones such as insulin, which helps to break down sugar. Pancreatic insufficiency is when the pancreas cannot produce or transport enough enzymes to the intestines to aid in the breakdown and absorption of food and nutrients.

Individuals with Alagille syndrome can also develop abnormalities of certain blood vessels (vascular anomalies) including those in the brain, liver, lungs, heart, and kidneys. Vascular anomalies in the brain can lead to bleeding inside the brain (intracranial bleeding) and stroke. Some individuals with Alagille syndrome have developed a condition known as Moyamoya syndrome. Moyamoya syndrome is a progressive disorder that is characterized by narrowing (stenosis) and/or closing (occlusion) inside the skull of the carotid artery, the major artery that delivers blood to the brain. Intracranial bleeding and other vascular anomalies are potentially life-threatening complications and account for a significant percentage of mortality and morbidity in Alagille syndrome.

Genetic disorders are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of a gene with a mutation is necessary for the appearance of the disorder. The gene with the mutation can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. If carried by a parent the risk of passing the gene with the mutation from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child. Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 20p12” refers to band 1, sub-band 2, on the short arm of chromosome 20. The numbered bands specify the location of the thousands of genes that are present on each chromosome. Alagille syndrome is caused by mutations in one of two genes – the JAG1 gene or the NOTCH2 gene. Mutations of the JAG1 gene have been identified in more than 88 percent of cases. Mutations in the NOTCH2 gene account for less than 1 percent of cases. These mutations are inherited as autosomal dominant traits. In some cases, the mutations occur randomly due to a spontaneous genetic change (i.e., new mutation).Investigators have determined that the majority of cases of Alagille syndrome occur due to mutations of the JAG1 gene located on the short arm (9) of chromosome 20 (20p12). In approximately 6-7 percent of Alagille syndrome cases, individuals have a complete deletion or loss of the JAG1 gene. These individuals may have a more severe form of Alagille syndrome depending on how large the deletion is and how many other genes on chromosome 20 are involved. Investigators have determined that the NOTCH2 gene is located on the short arm of chromosome 1 (1p13-p11).
Alagille syndrome affects males and females in equal numbers. The incidence of Alagille syndrome has been estimated to be approximately 1 in 30,000-45,000 individuals in the general population. Some cases of Alagille syndrome may go undiagnosed or misdiagnosed making it difficult to determine the true frequency of Alagille syndrome in the general population.
Symptoms of the following disorders can be similar to those of Alagille syndrome. Comparisons may be useful for a differential diagnosis.

Extrahepatic biliary atresia is a rare gastrointestinal disorder characterized by destruction or absence of all or a portion of the bile duct that lies outside the liver (extrahepatic bile duct). The bile duct is a tube that allows the passage of bile from the liver into the gall bladder and, eventually, the small intestine. Bile is a liquid secreted by the liver that plays an essential role in carrying waste products from the liver and breaking down fats in the small intestine. In extrahepatic biliary atresia, absence or destruction of the bile ducts results in the abnormal accumulation of bile in the liver. Affected infants may have yellowing of the skin and whites of the eyes (jaundice) and scarring of the liver (cirrhosis). Additional symptoms may include itching (pruritis), abnormal enlargement of the liver (hepatomegaly), pale or gray stools (acholic stools), and a swollen stomach. In some cases, additional abnormalities may be present, including heart defects and kidney and spleen malformations. The exact cause of extrahepatic biliary atresia is unknown. (For more information on this disorder, choose “extrahepatic biliary atresia” as your search term in the Rare Disease Database.)

Neonatal hepatitis refers to a group of liver disorders that affect newborns between the ages of about 1 and 2 months, and produce a typical yellow color to the infant’s skin (jaundice). In contrast to infants with Alagille syndrome, those with neonatal hepatitis have normal, intact bile ducts (biliary tracts). Symptoms may include an abnormal yellow discoloration of the skin and/or whites of the eyes (jaundice), pale stools, unusually dark urine, and/or abnormal enlargement of the liver (hepatomegaly). Infants with neonatal hepatitis may gain weight or grow at a slower than normal rate (failure to thrive). The infant may be irritable because of excessively itchy skin (pruritus). Additional symptoms may include abnormal enlargement of the spleen (splenomegaly) and the abnormal accumulation of body fluids within the abdomen (ascites). In many cases, the exact cause of neonatal hepatitis is unknown (idiopathic), although some cases seem to run in families. Some studies suggest an association with an infectious or viral disease. (For more information on this disorder, choose “idiopathic neonatal hepatitis” as your search term in the Rare Disease Database.)

Progressive familial intrahepatic cholestasis (PFIC) is a group of rare genetic disorders that affect the liver. The main symptom is the interruption or suppression of the flow of bile from the liver (cholestasis). Cholestasis occurs due to defects within the liver (intrahepatic). Additional symptoms may include yellowing of the skin, mucous membranes and whites of the eyes (jaundice), failure to thrive, growth deficiency, and severe itchiness (pruritus). The more severe forms of these disorders eventually progress to cause life-threatening complications such as scarring of the liver (cirrhosis) and liver failure.Velocardiofacial (VCFS) / DiGeorge syndrome is due to deletions of chromosome 22q11.2. Several clinical features that overlap with those seen in Alagille syndrome can be seen in individuals deleted for 22q11.2 including congenital heart defects (pulmonic stenosis, tetralogy of Fallot, etc), posterior embryotoxon and other anterior chamber defects of the eyes and butterfly vertebrae. Liver (hepatic) involvement is not typically seen in individuals with the 22q11.2 deletion syndrome. (For more information on this disorder, choose “Chromosome 22q11.2 deletion syndrome” as your search term in the Rare Disease Database.)

A wide variety of additional disorders and conditions can cause symptoms that are similar to those associated with Alagille syndrome. More than 100 different causes of cholestasis alone have been identified. Many other disorders can cause bile duct paucity including alpha-1-antitrypsin deficiency, cystic fibrosis, Zellweger spectrum disorders and various chromosomal, immunologic and infectious disorders. Most of these disorders have additional, distinctive symptoms or clinical findings that can distinguish them from Alagille syndrome. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)

A diagnosis of Alagille syndrome is made based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Because the symptoms of Alagille syndrome are highly variable, obtaining a diagnosis can be difficult. Surgical removal and microscopic study of liver tissue (liver biopsy) can reveal bile duct paucity. Although bile duct paucity is considered a key characteristic of Alagille syndrome, this finding is not always present in infants with the disorder.

A physician may suspect Alagille syndrome if an individual has three of the following five clinical findings in addition to bile duct paucity: symptoms of liver disease or cholestasis, heart defect, skeletal abnormality, eye (ophthalmologic) abnormality, and/or distinctive facial features.In addition to a liver biopsy, physicians may conduct other tests to aid in the diagnosis of Alagille syndrome. Such tests may include blood tests to determine liver function and detect fat-soluble vitamin deficiencies, an eye examination, x-rays of the spine to detect characteristic changes such as butterfly vertebrae, an abdominal ultrasound of the hepatobiliary tree (e.g., liver, pancreas, gall bladder and spleen) to detect abnormalities or rule out other conditions, and an examination of heart structure and function to detect potential heart abnormalities. The diagnosis of Alagille syndrome can be confirmed in many cases by molecular genetic testing, which reveals the presence of a JAG1 or NOTCH2 mutation. However, in some people with Alagille syndrome, genetic testing may not reveal a JAG1 or NOTCH2 mutation.

The treatment of Alagille syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, gastroenterologists, cardiologists, ophthalmologists, and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment. Individuals with Alagille syndrome should have a baseline echocardiogram (ultrasound of the heart) to screen for heart involvement, ultrasound of the abdomen to screen for liver and kidney anomalies, and a screening eye (ophthalmology) exam, In addition, if not previously obtained for specific symptoms, a screening imaging study of the blood vessels of the head (MRI/MRA) is recommended for children who are old enough to sit through the study without need for anesthesia or sedation. Supplemental treatment with vitamins and nutrients is essential for individuals with malabsorption. Such treatment may include restoring vitamins A, D, E and K. Young children may be given formula with medium chain triglycerides because this form of fat is better absorbed by individuals with Alagille syndrome who have cholestasis. In some cases, affected children may need to receive extra calories through a tube that runs from the nose to the stomach (nasogastric tube) or through a tube placed directly into the stomach through a small incision in the abdominal wall and stomach (gastrostomy tube).Specific treatment may be indicated for individuals with cholestatic liver disease. The drug ursodeoxycholic acid is given to help improve bile flow, which can lead to a reduction in some symptoms such as itching (pruritus) or fatty deposits (xanthomas). However, pruritus associated with Alagille syndrome often is resistant to therapy. Additional drugs that have been used to treat pruritus include antihistamines, rifampin, cholestyramine, and naltrexone. Keeping the skin properly hydrated with moisturizers is also recommended. Cholestyramine may also be indicated for individuals with elevated cholesterol levels or xanthomas.Some affected infants and children with Alagille syndrome who do not respond to pharmacologic and dietary therapies may be treated by a surgical procedure known as partial biliary diversion. This surgical procedure is used to disrupt or divert recirculation of bile acids between the liver and the gastrointestinal tract. This therapy has demonstrated that, in some cases, it can improve certain symptoms such as reducing itchiness or xanthoma formation.

In severe cases of Alagille syndrome (i.e., cases that have progressed to cirrhosis or liver failure or in which other therapies were unsuccessful), liver transplantation may be required.

Additional complications that can be associated with Alagille syndrome including heart, blood vessel and kidney abnormalities are treated in the standard manner. In some cases, this may include surgery.

Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll free: 800.411.1222
TTY: 866.411.1010
Email: prpl@cc.nih.gov.
For information about clinical trials sponsored by private sources, contact: www.centerwatch.com
For information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
Contact for more information about this condition:
Henry Lin, MD
Assistant Professor of Pediatrics
Division of Gastroenterology, Hepatology, and Nutrition The Children’s Hospital of Philadelphia linhc@mail.chop.edu
The Alagille Syndrome Alliance is a member organization of NORD. For more information about NORD, please visit https://rarediseases.org/rare-diseases/alagille-syndrome/.
American Liver Foundation
39 Broadway, Suite 2700
New York, NY 10006 USA
Toll-free: 800.465.4837
Email: http://www.liverfoundation.org/contact/
Website: http://www.liverfoundation.org
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Canadian Liver Foundation
3100 Steeles Avenue East Suite 801
Markham Ontario, L3R 8T3 Canada
Phone: 416.491.3353
Toll-free: 800.563.5483
Email: clf@liver.ca
Website: http://www.liver.ca
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Childhood Liver Disease Research and Education Network
c/o Joan M. Hines, Research Administrator
Children’s Hospital Colorado
Aurora, CO 80045
Phone: 720.777.2598
Email: joan.hines@childrenscolorado.org
Website: http://www.childrennetwork.org
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Children’s Liver Association for Support Services (C.L.A.S.S.)
25379 Wayne Mills Place, Suite 143
Valencia, CA 91355 USA
Phone: 661.263.9099
Toll-free: 877.679.8256
Email:info@classkids.org
Website: http://www.classkids.org
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Children’s Liver Disease Foundation o 36 Great Charles Street
Birmingham, B3 3JY United Kingdom
Phone: 121.212.3839
Email: info@childliverdisease.org
Website: http://www.childliverdisease.org
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Congenital Heart Information Network (C.H.I.N.)
P.O. Box 3397
Margate City, NJ 08402-0397
Phone: 609.823.4507
Email: mb@tchin.org
http://www.tchin.org
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Digestive Disease National Coalition
507 Capitol Court, NE
Suite 200
Washington, DC 20002
Phone: 202.544.7497
Email: ddnc@hmcw.org
Website: http://www.ddnc.org
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NIH/National Institute of Diabetes, Digestive & Kidney Diseases
Office of Communications & Public Liaison
Bldg 31, Rm 9A06
Bethesda, MD 20892-2560
Phone: 301.496.3583
Email: NDDIC@info.niddk.nih.gov
Website: http://www2.niddk.nih.gov
antssTextbooks
Jones KL. Ed. Smith’s Recognizable Patterns of Human Malformation. 6th ed. Elsevier
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Mulberg AE, Rovner A. Alagille Syndrome. NORD Guide to Rare Disorders. Lippincott
Williams & Wilkins. Philadelphia, PA. 2003:332-333.
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Rimoin D, Connor JM, Pyeritz RP, Korf BR. Eds. Emory and Rimoin’s Principles and
Practice of Medical Genetics. 4th ed. Churchill Livingstone. New York, NY; 2002:1222-
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antssJournal Articles
Kamath BM, Bauer RC, Loomes KM, Chao G, Gerfen J, Hutchinson A, Hardikar W,
Hirschfield G, Jara P, Krantz ID, Lapunzina P, Leonard L, Ling S, Ng VL, Hoang PL, Piccoli
DA, Spinner NB. NOTCH2 mutations in Alagille syndrome. J Med Genet. 2012;49:138-44.
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Penton AL, Leonard LD, Spinner NB. Notch signaling in human development and
disease. Semin Cell Dev Biol. 2012;23:450-7
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Emerick KM, Elias MS, Melin-Aldana H, et al. Bile composition in Alagille syndrome and
PFIC patients having partial exnternal biliary diversion. BMC Gastroenterol. 2008;8:47.
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Ling SC, Congenital cholestatic syndromes: what happens when children grow up? Can J
Gastroenterol. 2007;21:743-751.
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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;79:169-73.
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Warthen DM, Moore EC, Kamath BM, et al. Jagged1 (JAG1) mutations in Alagille
syndrome: increasing the mutation detection rate. Hum Mutat. 2006;27:436-443.
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Kamath BN, Spinner NB, Emerick KM, et al. Vascular anomalies in Alagille syndrome: a
significant cause of morbidity and mortality. Circulation. 2004;109:1354-1358.
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Emerick KM, Rand EB, Goldmuntz E, et al. Features of Alagille syndrome in 92 patients:
frequency and relation to prognosis. Hepatology. 1999;29:822-829.
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Li L, Krantz ID, Deng Y, et al. Alagille syndrome is caused by mutations in human
Jagged1, which encodes a ligand for Notch1. Nat Genet. 1997;
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Alagille D, Estrada A, Hadouchel M, et al. Syndromic paucity of interlobular bile ducts
(Alagille syndrome or arteriohepatic dysplasia): review of 80 cases. J Pediatr.
1987;110:195-200.
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antssInternet
Scheimann A. Alagille syndrome.Medscape,Updated January 10, 2016.. Available at:
http://emedicine.medscape.com/article/926678-overview Accessed March 17, 2016.
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Spinner NB, Leonard LD, Krantz ID. Alagille Syndrome. 2000 May 19 [Updated 2013 Feb
28]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet].
Seattle (WA): University of Washington, Seattle; 1993-2016. Available from:
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McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The
Johns Hopkins University; Entry No:118450; Last Update:1/30/2014. Available at:
http://www.ncbi.nlm.nih.gov/books/NBK1273/ Accessed March 17, 2016.
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McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The
Johns Hopkins University; Entry No:610205; Last Update:12/19/11. Available at:
http://omim.org/entry/610205 Accessed March 17, 2016.
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