What is Alagille syndrome?

Risk Factors

AGS is an autosomal dominant syndrome. Offspring of an affected parent are at 50 percent risk of having AGS. Inherited mutations are found in 30 to 50 percent of affected individuals. De novo mutations are seen in 50 to 70 percent of individuals with AGS. Parents of a child with a de novo mutation have a small risk for a second affected child because of germ-line mosaicism. The prevalence of AGS was estimated at 1 in 70,000. In 2003, B. M. Kamath et al. revised estimates to 1 in 30,000 to 50,000 live births. However, even this may be an underestimate as a result of the variable expressivity and reduced penetrance seen in this disorder.

Etiology and Genetics

AGS was shown to be autosomal dominant using family history. The syndrome was mapped to chromosome 20 by cytogenetic deletions found in individuals with AGS. Subsequently, the gene JAG1 (20p12) has been shown to be associated with AGS. More than four hundred mutations in JAG1 have been identified as causing AGS in about 89 percent of affected individuals. About 7 percent of affected individuals have a cytogenetically detectable microdeletion on chromosome 20p12 that includes the JAG1 gene. A second gene, NOTCH 2, which is found in the same pathway as JAG1, has recently been shown to be associated with about 1 to 2 percent of AGS families.

Symptoms

AGS is characterized by reduction in the number of bile ducts, leading to cholestasis (bile blockage). Since neonatal cholestasis is common, additional findings (unusual facies, eye, heart, and skeletal malformations) must be seen to make the diagnosis of AGS. Liver symptoms, present in the newborn, range from mild (jaundice) to severe (liver failure). According to N. Spinner, L. Leonard, and I. Krantz, about 15 percent of affected individuals will need liver transplantation. Conversely, a small number of individuals have no detectable liver disease. Cardiac defects are seen in more than 90 percent of AGS patients, the most common being tetralogy of Fallot (pulmonary stenosis and ventricular septal defect plus other abnormalities; 7–16 percent).

Posterior embryotoxon (a thickened ring around the cornea) is the most common eye defect (78–89 percent) seen in AGS; it is difficult to use this as a diagnostic tool, however, as 8 to 15 percent of the general population has posterior embryotoxon. Other common eye findings include both Axenfeld and Rieger anomalies. Although a large portion of patients with AGS have eye defects, most do not have vision problems.

The most common skeletal malformation is butterfly vertebrae (clefting of the vertebral body). Butterfly vertebrae are found in 33 to 93 percent of AGS patients and, although they cause no symptoms, provide a good diagnostic tool for affected patients and families. The unusual facies seen in AGS are characterized by a broad forehead, a saddle-shaped or straight nose with bulbous tip, a pointed chin, and deep-set eyes with moderate hypertelorism. This inverted triangular appearance is seen in more than 75 percent of affected individuals.

Early reports claimed that 30 percent of affected individuals had intellectual disability or developmental delay. A 1999 study by K. M. Emerick et al. found intellectual disability in 2 percent and developmental delay in 16 percent of affected individuals. This difference is believed to be the result of more aggressive nutritional management and intervention.

Less common findings associated with Alagille syndrome include renal abnormalities, pancreatic insufficiency, growth failure, neurovascular accidents, delayed puberty, high-pitched voice, and craniosynostosis.

Screening and Diagnosis

The most important feature of AGS is bile duct paucity. A clinical diagnosis can be made if an individual has three of five major clinical features (cholestasis, cardiac defect, butterfly vertebrae, eye abnormalities, unusual facies) and bile duct paucity. An individual with an affected first-degree relative and one or more of the five major clinical features also receives a diagnosis of AGS. To confirm this diagnosis, sequence analysis of the JAG1 gene should be considered first. If a JAG1 mutation is not identified, then fluorescence in situ hybridization (FISH) can be used to look for intragenic deletions. If deletions including JAG1 are identified, then a full cytogenetic study is warranted to rule out additional chromosomal translocations. This is especially important if developmental delay or intellectual disability are identified in an individual with AGS. Lastly, NOTCH2
genetic testing should be considered if all other molecular testing is negative but clinical suspicion remains high.

Treatment and Therapy

A multidisciplinary team is the best approach to management of individuals with AGS, including specialists in genetics, gastroenterology, nutrition, cardiology, and ophthalmology. Medication may be prescribed to improve bile flow and to reduce itching, if present. Mortality is 10 percent, with cardiac defects the cause of most neonate deaths. Liver failure and vascular accidents account for most later-onset morbidity and mortality. Liver transplantation has an 80 percent five-year survival rate. According to a 2010 study by J. Pawlowska, P. Socha, and I. Jankowska, moderate catchup growth and improved liver functions may be seen in transplanted patients. AGS patients with liver disease should avoid alcohol and contact sports. Cardiac disease can vary from asymptomatic, nonprogressive murmur to complex structural defects (such as tetralogy of Fallot) requiring surgical intervention. Growth in AGS individuals should be closely monitored. Because the diminished bile flow can inhibit the digestion of fats and absorption of fat-soluble vitamins, nutritional optimization should be used to maximize growth potential and prevent developmental delay. Head injuries and/or neurologic symptoms in individuals with AGS should be treated aggressively. Magnetic resonance imaging and magnetic resonance angiography can identify aneurysms, dissections, or bleeds in symptomatic individuals. These therapies are being debated for use in presymptomatic individuals with AGS.

Prevention and Outcomes

Genetic counseling, prenatal diagnosis, and preimplantation genetic diagnosis (PGD) are available to affected or at-risk family members for the prevention of AGS. Prenatal diagnosis and PGD are options in families and individuals with a molecular diagnosis.

Bibliography

"Alagille Syndrome." American Liver Foundation. Amer. Liver Foundation, 13 Nov. 2013. Web. 14 July 2014.

"Alagille Syndrome." National Digestive Diseases Information Clearinghouse. National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 29 Mar. 2013. Web. 14 July 2014.

Kamath, Binita M., Nancy B. Spinner, and David A. Piccoli. "Alagille Syndrome." Liver Diseases in Children. Ed. William F. Balistreri, Ronald J. Sokol, and Frederick J. Suchy. Cambridge: Cambridge UP, 2007. Print.

Kim, B. J., and A. B. Fulton. “The Genetics and Ocular Findings of Alagille Syndrome.” Seminars in Ophthalmology 22 (2007): 205–10. Print.

Pawlowska, J., P. Socha, and I. Jankowska. "Factors Affecting Catch-Up Growth after Liver Transplantation in Children with Cholestatic Liver Diseases." Annals of Transplantation 15.1 (2010): 72–76. Print.

Oda, T., A. G. Elkahloun, and B. L. Pike et al. “Mutations in the Human Jagged1 Gene Are Responsible for Alagille Syndrome.” Nature Genetics 16.3 (1997): 235–42. Print.

Spinner, Nancy B., Laura D. Leonard, and Ian D. Krantz. "Alagille Syndrome." GeneReviews. U of Washington, Seattle, 28 Feb. 2013. Web. 14 July 2014.