Alagille Syndrome

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Digestive system diagram showing bile duct location. Source: Wikimedia Commons (NIH/NIDDK).

Alagille syndrome is a genetic disorder that causes a loss of bile ducts in the liver and narrowing of the ducts outside the liver. The resulting buildup of bile in the liver can cause scarring and cirrhosis. Other features of this syndrome include abnormalities of the kidneys, cardiovascular system, eyes, and spine. The syndrome may also be associated with mental retardation and failure to thrive (growth delay).


Contents

  • 1 Other Names
    * 2 Signs and Symptoms
    * 3 Causes
    * 4 Diagnosis
    * 5 Treatment
    o 5.1 Medications
    o 5.2 Therapies
    o 5.3 Holistic and alternative treatments
    * 6 Chances of Developing Alagille Syndrome
    o 6.1 Heredity
    * 7 Related Problems
    o 7.1 Complications
    * 8 Clinical Trials
    * 9 Research
    o 9.1 Recent discoveries
    * 10 Expected Outcome
    * 11 History
    * 12 Epidemiology
    o 12.1 Prevalence
    * 13 References
    * 14 External Links

Other Names

  • Watson-Miller syndrome
    * Alagille-Watson Syndrome
    * Arteriohepatic dysplasia (AHD)
    * Cardiovertebral syndrome
    * Hepatic ductular hypoplasia
    * Hepatofacioneurocardiovertebral syndrome

Signs and Symptoms

Signs and symptoms arising from liver damage in Alagille syndrome may include jaundice, (a yellowish tinge in the skin and the whites of the eyes), pruritis (itching), and xanthoma (deposits of cholesterol in the skin).

Heart problems associated with Alagille syndrome may include pulmonic stenosis, ventricular septal defect and other problems in a condition called tetralogy of Fallot.

Children with Alagille syndrome may have an extra, circular line on the surface of the eye called a posterior embryotoxon. They may also have pigment changes of the retina. Both abnormalities can be detected during a specialized eye examination.

Characteristic facial features include a broad, prominent forehead, deep-set eyes, and a small pointed chin.

The disorder may also affect the kidneys and central nervous system, and cause an unusual butterfly shape of the bones of the spinal column that can be seen in an x-ray.

The presenting symptoms are most often jaundice and failure to thrive in infancy.
Causes

Mutations in the JAG1 and NOTCH2 genes cause Alagille syndrome. These genes provide instructions for making proteins that fit together to trigger signaling between neighboring cells during embryonic development. This signaling influences how the cells are used to build body structures in the developing embryo. Mutations in either the JAG1 gene or NOTCH2 gene probably disrupt the signaling pathway. As a result, errors may occur during development, especially affecting the heart, bile ducts in the liver, spinal column, and certain facial features. Mutations in NOTCH2 are observed in fewer than 1% of individuals with AGS. [1]
Diagnosis

The syndrome is usually suspected when a patient presents with many or all of the distinct findings, including reduced bile flow, congenital heart disease, bone defects, a thickening of a line on the surface of the eye, and particular facial features. Diagnosis can be confirmed by genetic analysis.

Some of the tests involved in the diagnosis of Alagille syndrome include: [2]

  • Blood Tests - may include CBC (complete blood count), LFTs (liver function tests) and PT/PTTs (blood clotting factors).
    * Liver Biopsy- Removal and examination of a small sample of liver tissue.
    * Ultrasound - Identifies any obvious abnormalities in the liver and other organs.
    * Nuclear Scan - Determines how much, if any, bile is flowing from the liver.
    * Exploratory Surgery - Performed to examine the liver and bile ducts.

Treatment

There is no cure for Alagille syndrome. The following may help with symptom relief:
Medications

Therapy with antihistamines may provide some relief from the itching associated with liver disease. The medicines rifampin or naltrexone may also be helpful.

Ursodeoxycholic acid may help increase bile flow in the liver.
Therapies

Heart surgery may be needed depending on the specific condition. Liver transplantation may also be a surgical option for some patients.
Holistic and alternative treatments

Because children with Alagille syndrome may develop fat-soluble vitamin (A, D, E and K) deficiencies, it is important to have the vitamin D level in their blood checked. Calcium supplementation may also be needed.
Chances of Developing Alagille Syndrome
Heredity

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

In approximately 30 to 50% of cases, an affected person inherits the mutation from one affected parent. Other cases result from new mutations in the gene. These cases occur in people with no history of the disorder in their family.

The offspring of an individual with Alagille syndrome have a 50% chance of having Alagille syndrome. Prenatal testing is possible if a mutation in JAG1 is identified in an affected family member. Although testing can determine whether or not the fetus has inherited the JAG1 disease-causing mutation or deletion, it cannot predict the occurrence or severity of clinical manifestations. Prenatal testing for Alagille syndrome caused by mutations in NOTCH2 may be available through laboratories offering custom prenatal testing. [1]
Related Problems
Complications

Because Alagille syndrome causes problems with the bile ducts, the result is liver cirrhosis and scarring. In addition, this syndrome causes abnormalities of the kidneys, problems with the cardiovascular system, as well as abnormalities of the eyes and spine. The syndrome may also be associated with mental retardation and failure to thrive (growth delay).

Intracranial bleeding (bleeding within the skull) is the most dangerous central nervous system complication of Alagille syndrome and is a major cause of morbidity and mortality. It occurs in approximately 15% of people with AGS, and in 30 to 50% of these events the bleed is fatal. [6] The majority of these events are spontaneous, although some have occurred after minor head trauma. It is not possible to predict who is at risk for developing a bleed. In addition to bleeding within the head, blood vessel problems such as aneurysms (dilatations) and stenoses (narrowings) can also be seen elsewhere in the body, such as kidney vessels and the aorta.
Clinical Trials

An ongoing trial involving Alagille syndrome is available at ClinicalTrials.gov: Evaluating the Genetic Causes and Progression of Cholestatic Liver Diseases
Research
Recent discoveries

  • A study was done in Mexico to determine if first degree relatives of patients with Alagille syndrome had higher than expected amount of lipids in the blood. This was not found to be the case. [3]
    * The Notch2 gene and its relevance in vascular smooth muscle development and the cardiac abnormalities associated with Alagille syndrome are discussed. [4]
    * The opthamologic abnormalities associated with Alagille syndrome are described. [5]

Expected Outcome

Intracranial bleeding (bleeding within the skull) is the most dangerous central nervous system complication of Alagille syndrome and is a major cause of morbidity and mortality. It occurs in approximately 15% of people with AGS, and in 30 to 50% of these events the bleed is fatal. [6] The majority of these events are spontaneous, although some have occurred after minor head trauma. It is not possible to predict who is at risk for developing a bleed. In addition to bleeding within the head, blood vessel problems such as aneurysms (dilatations) and stenoses (narrowings) can also be seen elsewhere in the body, such as kidney vessels and the aorta.
History

Alagille Syndrome was named for Dr. Daniel Alagille, a French hepatologist who described the associated characteristics of hepatic duct hypoplasia, cardiac abnormalities, charactaristic facial abnormalities, mental and growth retardation in the Journal of Pediatrics in 1975. [7]
Epidemiology
Prevalence

The estimated prevalence of Alagille syndrome is 1 in every 70,000 people. This figure is based on diagnoses of liver disease in infancy, and may be an underestimation due to the varying severity and symptoms of the disorder. The prevalence of this disorder could be as high as 1 in 20,000 people if the frequency of gene mutations that cause Alagille syndrome is considered.
References

1. ↑ 1.0 1.1 Spinner N, Krantz I, Kamath B. Alagille Syndrome. Gene Reviews. May 19, 2000.
2. ↑ Liverkids.org. Alagille's Syndrome
3. ↑ Larrosa-Haro A, Melgoza-Radillo M, Sánchez-Ramírez CA, Hurtado-López EF. Serum lipids in parents and siblings of children with Alagille syndrome: a pilot study. Hepatogastroenterology.2008 Jan-Feb;55(81):1-3. Abstract
4. ↑ Varadkar P, Kraman M, Despres D, Ma G, Lozier J, McCright B. Notch2 is required for the proliferation of cardiac neural crest-derived smooth muscle cells. Dev Dyn. 2008 Apr;237(4):1144-52. Abstract
5. ↑ Kim BJ, Fulton AB. The genetics and ocular findings of Alagille syndrome. Semin Opthamol. 2007 Oct-Dec;22(4):205-10. Abstract
6. ↑ The Childrens Hospital of Philadelphia web site. Vascular Problems and Alagille Syndrome
7. ↑ Alagille D, Odiévre M, Gautier M, Dommergues JP. Hepatic ductular hypoplasia associated with characteristic facies, vertebral malformations, retarded physical, mental, and sexual development, and cardiac murmur. J Pediatr. 1975 Jan;86(1):63-71. Abstract

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