Alagille syndrome is a genetic condition characterized by liver disease, typical facial features, heart murmurs or defects, vertebral changes, and eye changes as well as a variety of less frequently noted features. Alagille syndrome is also called arteriohepatic dysplasia , cholestasis with peripheral pulmonary stenosis, syndromatic hepatic ductular hypoplasia, and Alagille-Watson syndrome.
Alagille syndrome is a rare condition occurring either sporadically or in an autosomal dominant pattern of inheritance . Approximately 70% of cases are caused by changes in the Jagged1 gene on chromosome 20. However, the diagnosis of Alagille syndrome is based on clinical features and family history. Obtaining medical information about family members can be difficult as some people with Alagille syndrome are so mildly affected or have variable symptoms that the condition may go unrecognized. Prognosis depends on the extent of major organ involvement, especially of the liver, heart, and kidneys. Liver transplantation is needed in some cases. Prenatal testing is available to families in which a genetic change has been identified. The interpretation of this testing is limited by the variability of clinical features, even within the same family. People with the same genetic change can have a wide range of medical problems with varying degrees of severity.
Alagille syndrome occurs sporadically in 15-56% of cases, but has been noted to follow an autosomal dominant pattern of inheritance in some families. In sporadic cases, the gene change occurred for the first time in the affected individual, and neither parent has the same gene change. In autosomal dominant inheritance, multiple generations of a family are affected with the condition. In either case, people who have the genetic change have a 50% chance to pass the altered gene on to each of their children. Since the gene is dominant, passing on one copy of the gene is enough to cause symptoms. However, the condition exhibits variable expressivity. This means that different people with the condition may experience different features of the disease or levels of severity. One explanation for this is that different changes in the gene may cause different features of the syndrome. However, even in families that all have the same genetic change, different features and degrees of severity can occur. In addition, the condition is not fully penetrant. Some people who have the gene change, due to an affected parent and child, do not show any features of the disease.
Changes in a gene called the Jagged1 (Jag1) gene on the short arm of chromosome 20 have been shown to be the underlying defect in many patients. The Jag1 gene encodes a cell surface protein that plays a role in the regulation of development. The protein is active in many cell types and directs cells to their proper place in the embryo. Seventy to 75% of Alagille syndrome probands have had an identifiable change within this gene. Of that 70%, 6% have been shown to have a small deletion of a piece of the short arm of chromosome 20 (20p), which includes the Jag1 gene, using a laboratory technique called fluorescent in situ hybridization. There are a variety of other molecular changes in the gene that have been detected by sequencing the gene. Thirty percent of people with the condition do not have an identifiable change in this gene. It is possible that there are other genes that cause the disease in these families.
Alagille syndrome is rare, occurring in one in 70,000-100,000 live births. The condition affects males and females equally. Most patients with Alagille syndrome come to medical attention in the first four months of life with jaundice, an enlarged liver, severe itching of skin, or multiple raised nodular areas on the skin.
Signs and symptoms
One of the most common and most serious symptoms of Alagille syndrome is liver disease. Liver disease occurs in 90-100% of patients and often leads to growth delay or failure as a result of malnutrition. Because there is a reduction in the number of bile ducts in the liver, there are elevated bile acids in the blood and an arrest of bile excretion from the body. This results in jaundice, pruritus (severe skin itching), and xanthomas (raised nodules on the skin, especially at skin creases or areas of friction). Some patients have mild or no liver problems, while others have progressive liver failure.
Heart defects and murmurs have been noted in 85-95% of patients with Alagille syndrome. The most common type of defect is pulmonary artery stenosis, although other types of defects also occur. Many of these defects do not have clinical significance to the patient. However, complex and severe heart defects occur and are one of the more common causes of mortality in patients with Alagille syndrome.
An important diagnostic feature of Alagille syndrome is a particular eye finding called posterior embryotoxon. This is an anterior chamber defect of the eye caused by a prominent, centrally positioned Schwalbe ring. This feature can be seen through a split lamp examination and does not affect vision. Since 56-90% of patients have this or other changes in the eye, including retinal pigmentary changes, an eye examination can aid in diagnosis.
A particular finding called a butterfly vertebra is associated with Alagille syndrome. The term butterfly vertebra refers to the appearance of the space around the vertebrae due to clefting or disruption of formation of a vertebra. There are usually no physical problems associated with this radiological finding. The frequency of butterfly vertebrae in this syndrome is uncertain, with estimates from 33-87% in different studies. Other skeletal malformations are also noted in these patients, such as spina bifida occulta and hemivertebrae. Therefore, radiological examination of the spine may aid in diagnosis.
The occurrence of particular facial features has been noted in 70-95% of patients with Alagille syndrome. The facial features include a prominent forehead, deep-set and widely spaced eyes, a pointed chin, and a straight nose with a bulbous tip. These features are more subjective, but one of the most consistent features of the diagnosis.
Problems with the structure and function of kidneys have been noted with an occurrence of 40-70%. Most often symptoms are mild, but renal disease has caused mortality in severe cases. Mild delays in gross motor function have been noted in 16% of children. Most of these children were those with severe organ disease. Intracranial bleeding has also been noted with increased frequency and is associated with mortality in this syndrome.
The diagnosis of Alagille syndrome is based on clinical features and can be made by the presence of liver disease plus two of the other major features. An ultrasound of the liver can rule out other causes of liver disease and a liver biopsy can determine if there is a reduction in the number of bile ducts. However, this finding occurs in other conditions as well as Alagille syndrome, and the timing of the biopsy is important. Older patients are more likely to have fewer bile ducts than patients under five years of age. An echocardiogram for heart defects, a radiological examination of the spine, blood tests for renal function, an ophthalmologic examination, and an examination of facial features are important diagnostic tools. A careful family history is also important in diagnosis. When a first- or second-degree relative has already been diagnosed with Alagille syndrome, the presence of even one feature of the condition may constitute a diagnosis.
Once a diagnosis has been made in an individual, the parents should undergo an evaluation for subtle features of the condition. If a parent is diagnosed, then evaluation for appropriate extended family members would be offered. A correct diagnosis is important since there are other syndromes that exhibit similar liver disease, heart defects, and eye findings. These syndromes are inherited in different ways, so the recurrence risk for offspring and other family members may be different.
Two different types of testing are used: flourescence in situ hybridization (FISH), which detects the small percentage of patients who have a deletion of the entire gene; and sequencing, which looks at changes within the gene. Sequencing is not clinically available. New technologies may make gene sequencing for mutations more readily available in the near future. If a genetic change is identified in the family, prenatal testing would be available through chorionic villus sampling or amniocentesis . However, the interpretation of this testing is difficult since the presence of a gene change does not allow one to predict the severity of the condition or which medical problems may occur.
Treatment and management
Liver transplantation is needed in 15-20% of patients. Other treatments depend on which of the other features of the condition are present and the degree of severity. Repair of heart defects is another surgical treatment needed in some cases.
Prognosis for Alagille syndrome is quite variable and depends on the degree of liver, heart, and kidney disease and the presence of intracranial bleeding. Overall, survival rates are 72-85%. The survival rate of those undergoing liver transplantation is 60-80%. There is currently no method to determine which patients will reach end-stage liver disease.
Jones, Kenneth Lyons. Smith's Recognizable Patterns of Human Malformation. 5th ed. Philadelphia: W.B. Saunders, 1997.
Scriver, Charles, et al. The Metabolic and Molecular Bases of Inherited Disease. 8th ed. McGraw-Hill, 2001.
Emerick, Karan, et al. "Features of Alagille Syndrome in 92 Patients: Frequency and Relation to Prognosis." Hepatology (1999): 822-828.
Krantz, Ian, et al. "Alagille Syndrome." Journal of Medical Genetics (February 1997): 152-157.
Krantz, Ian, et al. "Clinical and Molecular Genetics of Alagille Syndrome." Current Opinions in Pediatrics (December 1999): 558-563.
Quiros-Tejeira, Ruben, et al. "Variable Morbidity in Alagille Syndrome: A Review of 43 Cases." Journal of Pediatric Gastroenterology and Nutrition (October 1999): 431-437.
Rand, Elizabeth. "The Genetic Basis of Alagille Syndrome." Journal of Pediatric Gastroenterology and Nutrition (February 1998): 234-237.
Sonja Rene Eubanks