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Alagille syndrome

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Related Terms
  • AHD, Alagille syndrome 1, Alagille's syndrome, Alagille-Watson syndrome, ALGS, ALGS1, anomalies of the optic disc, aortic aneurysms, arterioheptaic dysplasia, AS, ASD, atrial septal defect, autosomal dominant, AWS, Axenfeld anomaly, basilar artery aneurysms, butterfly-like vertebrae, cardiac disease, cardiovertebral syndrome, cholestasis with peripheral pulmonary stenosis arteriohepatic dysplasia and hepatic ductular hypoplasia, cholestatic liver disease, chronic cholestasis, coarctation of the aorta, dominant negative effect, glomerulosclerosis, growth hormone resistance, haploinsufficiency, heart defects, hepatic ductular hypoplasia, hepatofacioneurocardiovertebral syndrome, hepatosplenomegaly, hypoplasia of the hepatic ducts, inherited genetic disease, intellectual disability, internal carotid artery anomalies, iris attachment to Descemet membrane, JAG1 gene, Jagged1, lipoid nephrosis, liver defects, middle cerebral artery aneurysm, Moyamoya disease, NOTCH2 gene, occult renal artery stenosis, PA, papillary abnormalities, patent ductus arteriosus, paucity of interlobular bile ducts, PDA, peripheral pulmonary stenosis, posterior embryotoxon, pulmonary atresia, pulmonary valvular stenosis, renal artery stenosis, renal disease, retinitis pigmentosa, rickets, right-sided heart disease, syndromic bile duct paucity, tetralogy of Fallot, ventricular septal defect, VSD, Watson-Miller syndrome.

Background
  • Alagille syndrome is a rare genetic disorder that affects multiple systems in the body. The five major signs and symptoms associated with Alagille syndrome are problems with the bile ducts, which carry bile from the liver to the gallbladder and small intestine to help digest fats, narrowing of the main artery from the heart to the lungs, abnormal vertebrae, eye problems, and characteristic facial features. People with three of these five main signs are considered to have the syndrome. Additional signs and symptoms may involve the veins, bones, ears, pancreas, kidney, and intestine. Symptoms may vary widely among patients, even among members of the same family.
  • Alagille syndrome is caused by mutations or defects in the JAG1 and NOTCH2 genes. Mutations in the JAG1 gene cause the majority of cases, while mutations in the NOTCH2 gene cause fewer than 1% of cases. These genes provide the instructions for making proteins that play a role in communication between cells during fetal development. The mutations disrupt this communication and cause errors in development.
  • Alagille syndrome is inherited, or passed down from parent to child. The syndrome follows an autosomal dominant pattern of inheritance, meaning that only one copy of the defective gene is necessary for the disease to appear. There are about 226 genetic mutations, or abnormalities, associated with Alagille syndrome. About 70% of cases of Alagille syndrome are associated with known mutations. About 30% of cases of Alagille syndrome, however, have unknown causes. In about 30-50% of cases of Alagille syndrome, a person inherits the disorder from a parent. The remaining cases appear to result from a spontaneous mutation in the egg or sperm cells or in the developing embryo.
  • The incidence of Alagille syndrome is estimated to be about one in 70,000 live births worldwide. Some researchers state that the incidence may be higher due to unreported cases of the disease. Others estimate that the prevalence may be as high as one in 20,000 live births. Alagille syndrome appears to affect males and females in equal numbers. No particular race or ethnic group appears to be affected more than any other.
  • People are often diagnosed with Alagille syndrome early in life, when symptoms are first apparent. About 10% of people with Alagille syndrome die from complications of the disease. This may be caused by severe heart or liver disease early in life, or by heart attack or stroke later in life.
  • There is no cure for Alagille syndrome. Treatment focuses on reduction of symptoms and prevention and management of complications. If managed properly, most people with Alagille syndrome can have normal life spans.

Diagnosis
  • General: Most children with Alagille syndrome are evaluated for liver or heart problems by six months of age. Sometimes, family members with less severe symptoms may be diagnosed after a family member with a more severe form of the disease is diagnosed. Diagnosis of Alagille syndrome may be difficult, because of the wide variability of symptoms.
  • The five major symptoms associated with Alagille syndrome are chronic problems with the bile ducts, narrowing of the main artery from the heart to the lungs, abnormal vertebrae, eye problems, and distinctive facial features. People with three of these five main symptoms are considered to have the syndrome. After diagnosis of Alagille syndrome, patients should be regularly followed by a gastroenterologist, cardiologist, ophthalmologist, and kidney specialist.
  • Blood tests: A sample of blood may be drawn to measure levels of the fat-soluble vitamins A, D, E, and K. Inadequate bile in patients with Alagille may cause reduced absorption of fat-soluble vitamins, resulting in decreased levels. High levels of cholesterol and triglycerides in the blood are other common features of Alagille syndrome caused by cholestasis. Other considerations may include measurements of clotting, enzyme levels, bilirubin, bile acids, and anemia.
  • Echocardiogram: An echocardiogram, which uses sound waves to create a moving picture of the heart, can be used to test for abnormal heart structure and function.
  • Eye exam: An eye exam using a special piece of equipment known as a slit lamp may be used to provide a magnified, three-dimensional view of the different parts of the eye to check for abnormalities.
  • Genetic testing: If Alagille syndrome is suspected, a genetic test may be performed to confirm a diagnosis. A sample of the patient's blood is taken and analyzed in a laboratory for defects in the JAG1 or NOTCH2 genes. If these are detected, a positive diagnosis is made.
  • Imaging studies: Ultrasound uses sound waves to create pictures of the structures inside the body and may be used to assess the health of the liver, kidneys, and spleen. An ultrasound done during pregnancy may be able to detect the heart problems associated with Alagille syndrome in a developing fetus. X-ray imaging may help a clinician assess the shape of the vertebrae or bones that make up the spinal column. Imaging studies can be used throughout the course of the disease to periodically assess the health and function of the blood vessels, heart, liver, and kidneys.
  • An endoscopic retrograde cholangiopancreatography (ERCP) is a type of imaging study that allows a clinician to assess the health and function of the liver, gallbladder, bile ducts, and pancreas. An ERCP combines the use of X-rays and an endoscope, which is a long, flexible, lighted tube that is inserted into the mouth and down the throat. Before the exam, the patient is given certain drugs (anesthetics) to numb the back of the throat and aid in relaxation. The patient then swallows the endoscope so a clinician may view the inside of the stomach and upper small intestine. Dyes may be injected through the tube so that other parts of the digestive tract, such as the pancreas and bile ducts, may be visible in an X-ray.
  • Liver biopsy: In a biopsy, a small sample of tissue is removed for analysis in a laboratory. In Alagille syndrome, it may be necessary to acquire a liver biopsy to assess the bile ducts. Liver biopsy findings may vary depending on the age of the patient and the stage and severity of the disease. A liver biopsy done on a newborn may not reveal findings characteristic of Alagille syndrome and may lead to misdiagnosis. Because problems with the bile ducts do not occur only in Alagille syndrome, other tests may be needed to verify the cause of this symptom.
  • Prenatal DNA testing: If there is a family history of Alagille syndrome, prenatal testing may be performed to determine whether the fetus has the disorder. Amniocentesis and chorionic villus sampling (CVS) can diagnose Alagille syndrome. However, because there are serious risks associated with these tests, patients should discuss the potential health benefits and risks with a medical professional.
  • During amniocentesis, a long, thin needle is inserted through the abdominal wall and into the uterus, and a small amount of amniotic fluid is removed from the sac surrounding the fetus. Cells in the fluid are then analyzed for normal and abnormal chromosomes. This test is performed after 15 weeks of pregnancy. The risk of miscarriage is about one in 200-400 patients. Some patients may experience minor complications, such as cramping, leaking fluid, or irritation where the needle was inserted.
  • During chorionic villus sampling (CVS), a small piece of tissue (chorionic villi) is removed from the placenta between the ninth and 14th weeks of pregnancy. CVS may be performed through the cervix or through the abdomen. The cells in the tissue sample are then analyzed for a mutation in the JAG1 or NOTCH2 genes. Miscarriage occurs in about 0.5%-1% of women who undergo this procedure.

Complications
  • Heart disease: Narrowing of the blood vessels and high levels of cholesterol and triglycerides in the blood can lead to heart disease in patients with Alagille syndrome.
  • Kidney disease: Problems with the kidneys, including narrowing of the renal artery, having a single kidney, and structural malformations, may occur in patients with Alagille syndrome. Scarring and hardening of the blood vessels in the kidney can also lead to complications. This causes protein to be excreted in the urine and further kidney damage.
  • Liver: Complications that result from the inability of bile to be delivered from the liver into the small intestine include jaundice (yellowing) of the skin and whites of the eyes, cirrhosis, and liver failure.
  • Although the exact cause is not known, there have been several reports of hepatocellular carcinoma, a type of liver cancer, in patients with Alagille syndrome.
  • Skeletal: If vitamin deficiencies are not recognized, patients with Alagille syndrome may develop osteopenia, or low bone density, which increases the risk of fracture.
  • Vision: Although eye symptoms of Alagille syndrome do not typically affect vision, visual impairment has been observed in patients with intracranial hypertension high blood pressure in the brain).
  • Other: Other complications that may be seen in Alagille syndrome include anemia (low levels of red blood cells), bleeding in the brain, and severe itching of the skin.

Treatment
  • General: There is no cure for Alagille syndrome. Treatment focuses on the relief of symptoms and the prevention and management of complications. Treatment strategies for people with Alagille syndrome should include the expertise of a geneticist, physician, gastroenterologist, nutritionist, cardiologist, ophthalmologist, and liver transplant specialist. Growth should be monitored using standard growth charts, and nutritional intake should be modified based on this information.
  • Diet: People with Alagille syndrome tend to absorb nutrients better when the diet is higher in carbohydrates and medium-chain triglycerides. Patients who are underweight may benefit from high-calorie supplements or overnight tube feeding. In addition, patients should receive supplementation with the fat-soluble vitamins A, D, E, and K. Zinc supplementation may also be necessary in some patients.
  • Drugs: Most medications used in Alagille syndrome treat the discomfort associated with itching of the skin. Drugs that stimulate bile, such as ursodeoxycholic acid (Actigall®), can help treat the symptoms of itching and cholesterol deposits under the skin. Rifampin (Rifadin®, Rimactane®) and antihistamines such as hydroxyzine (Atarax®, Vistaril®) and diphenhydramine may also help with itching. Liver function should be closely monitored in patients taking rifampin, because of the potential for liver damage.
  • Cholesterol-lowering medications such as cholestyramine (Questran®) can be used in patients with high blood cholesterol levels. These medications may worsen fat-soluble vitamin deficiencies, however, and should be used with caution in patients with Alagille syndrome. Prescription-strength versions of the fat-soluble vitamins A, D, E, and K and minerals such as zinc may also be prescribed.
  • All patients with Alagille syndrome, except those with narrowing of the artery to the lungs, should also receive antibiotics that protect against an infection of the heart called subacute bacterial endocarditis.
  • Liver transplantation: Patients with Alagille syndrome with severe liver disease may benefit from liver transplantation. Liver transplantation should be considered if a patient has progressively worsening liver function, high blood pressure in the main vein leading from the liver to the heart, failure to thrive in infants, and severe itching that does not respond to other treatments. Liver transplantation is a complex procedure that may be associated with several complications, including organ rejection. About 80% of people who have successful liver transplants survive for five years after the procedure. Improved liver function and some catch-up growth may be observed in these patients.
  • Occupational therapy: Patients with Alagille syndrome may benefit from occupational therapy. During sessions, a therapist helps the child learn skills to help him or her perform basic daily tasks, such as eating, dressing, and communicating with others. Parents and caregivers can ask their children's pediatricians to recommend a therapist.
  • Spleen guard: Patients with an enlarged spleen should wear a padded spleen guard to protect the organ and surrounding areas from traumatic injury.
  • Surgery: A procedure called biliary diversion, in which a connection is made between the gallbladder and the skin so that bile may be drained to the outside of the body, may help reduce the severe itching that some patients experience. Patients with more severe forms of Alagille syndrome may require heart surgery to correct structural and functional problems in the heart.
  • Vaccinations: Vaccinations for hepatitis B, hepatitis A, and Pneumovax may decrease the risk of complications from chronic liver disease.
  • Other: Individuals with severe heart disease are often advised to avoid physical activity. Individuals with an enlarged spleen should avoid rough contact sports such as football. Individuals with liver disease should avoid alcohol consumption.

Author information
  • This information has been edited and peer-reviewed by contributors to the Natural Standard Research Collaboration (www.naturalstandard.com).

Bibliography
  1. Alagille Syndrome Alliance. .
  2. Alessandro G, Incerti M, Andreani M. Alagille syndrome: prenatal sonographic findings. J Clin Ultrasound. 2007 Mar-Apr;35(3):156-8.
  3. Dyack S, Cameron M, Otley A, et al. An autosomal recessive form of Alagille-like syndrome that is not linked to JAG1. Genet Med. 2007 Aug;9(8):544-50.
  4. Goldmuntz E, Moore E, Spinner NB. The cardiovascular manifestations of Alagille syndrome and JAGI mutations. Methods Mol Med. 2006;126:217-31.
  5. Kim BJ, Fulton AB. The genetics and ocular findings of Alagille syndrome. Semin Ophthalmol. 2007 Oct-Dec;22(4):205-10.
  6. Ling SC. Congenital cholestatic syndromes: what happens when children grow up? Can J Gastroenterol. 2007 Nov;21(11):743-51.
  7. Nagasaka H, Miida T, Hirano KI, et al. Fluctuation of lipoprotein metabolism linked with bile acid-activated liver nuclear receptors in Alagille syndrome. Atherosclerosis. 2008 Feb 29;
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  9. Schwartz R, Rehder K, Parsons DJ, et al. Intense pruritus and failure to thrive in Alagille syndrome. J Am Acad Dermatol. 2008 Feb;58(2 Suppl):S9-11.

Causes
  • General: Alagille is a rare, inherited genetic disorder caused by mutations or defects in the JAG1 and NOTCH2 genes. Mutations in the JAG1 gene cause the majority of cases, while mutations in the NOTCH2 gene cause fewer than 1% of cases. There are about 226 different types of genetic mutations in these genes that are associated with Alagille syndrome. About 70% of cases of Alagille syndrome are associated with known mutations. About 30% of cases of Alagille syndrome, however, have unknown causes.
  • Inheritance: In about 30-50% of cases of Alagille syndrome, a person inherits the disorder from a parent. When inherited, the syndrome follows an autosomal dominant pattern of inheritance. Individuals receive two copies of most genes, one from the mother and one from the father. For a person to inherit a dominant disorder, only one copy of the disease-causing gene is necessary. If one parent has the disorder, there is a 50% chance that the child will have the disorder. If both parents have the disorder, there is a 75% chance that the child will have the disorder.
  • Random occurrence: About 50-70% of cases of Alagille syndrome occur in individuals with no family history of the disease. These cases are caused by a spontaneous mutation in the egg or sperm cells, or in the developing embryo. These individuals can pass the disorder on to their children.

Risk factors
  • Because Alagille syndrome is inherited, a family history of the disease is the only known risk factor. In about 30-50% of cases of Alagille syndrome, a person inherits the disorder from a parent. The remainder of cases appears to result from a spontaneous mutation in the egg or sperm cells or in the developing embryo. A child of a person with Alagille syndrome has about a 50% chance of inheriting the disorder.
  • The incidence of Alagille syndrome is estimated to be about one in 70,000 live births. Some researchers believe that the incidence may be higher because of unreported cases of the disease. Others estimate that the prevalence may be as high as one in 20,000 live births. Alagille syndrome appears to affect males and females in equal numbers. No particular race or ethnic group appears to be affected more than any other.

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The information in this monograph is intended for informational purposes only, and is meant to help users better understand health concerns. Information is based on review of scientific research data, historical practice patterns, and clinical experience. This information should not be interpreted as specific medical advice. Users should consult with a qualified healthcare provider for specific questions regarding therapies, diagnosis and/or health conditions, prior to making therapeutic decisions.