eMedicine Specialties > Pediatrics: General Medicine > Gastroenterology

Alagille Syndrome

Author: Ann Scheimann, MD, MBA, Associate Professor, Department of Pediatrics, Section of Nutrition and Gastroenterology, Baylor College of Medicine and Johns Hopkins Medical Institution
Contributor Information and Disclosures

Updated: Oct 22, 2009

Introduction

Background

Alagille syndrome (AS) is an autosomal dominant disorder (OMIM 118450) associated with abnormalities of the liver, heart, skeleton, eye, and kidneys and a characteristic facial appearance.1 In 1973, Watson and Miller reported 9 cases of neonatal liver disease with familial pulmonary valvular stenosis.2 Then in 1975, Alagille et al described several patients with hypoplasia of the hepatic ducts with associated features.3

Typical facial features of Alagille syndrome. Not...

Typical facial features of Alagille syndrome. Note broad forehead, deep-set eyes and pointed chin.

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Typical facial features of Alagille syndrome. Not...

Typical facial features of Alagille syndrome. Note broad forehead, deep-set eyes and pointed chin.


Pathophysiology

Alagille syndrome is an autosomal dominant disorder with variable expression. Associated abnormalities include those of the liver, heart, eye, skeleton, and kidneys and characteristic facial features. Mild-to-moderate mental retardation also may be present. Mutations in either jagged-1 (JAG1) or notch-2 (NOTCH2) have been reported in patients with Alagille syndrome.4,5 The syndrome has been mapped to the 20p12-jagged-1 locus, JAG1, which encodes a ligand critical to the notch gene–signaling cascade that is important in fetal development.6,5 A minority (6-7%) of patients have complete deletion of JAG1, and approximately 15-50% of mutations are spontaneous.

Frequency

United States

The incidence rate is approximately 1 case in every 100,000 live births.

Mortality/Morbidity

Major contributors to morbidity arise from bile duct paucity or cholestatic liver disease, underlying cardiac disease, CNS vasculopathy, Moyamoya disease, and renal disease.

Sex

No difference in penetrance is reported.

Age

Most children are evaluated when younger than 6 months for either neonatal jaundice (70%), or cardiac murmurs and symptoms (17%). Patients who are less affected, such as family members, are often diagnosed after an index case.

Clinical

Physical

Presentation of Alagille syndrome (AS) varies. Some patients are diagnosed after prolonged neonatal jaundice or when liver biopsy findings reveal paucity of intrahepatic bile ducts. Others may be diagnosed during evaluation for right-sided heart disease. Some individuals are diagnosed by careful examination after an index case is identified in the family.

  • Nutrition and growth
    • Children often present with poor linear growth.
    • Altered longitudinal growth is attributed to wasting or inadequate intake, and an element of growth hormone resistance may also be present.7 Studies to assess the impact of higher doses of growth hormone on linear growth in patients with Alagille syndrome are currently underway.
  • Head and neck
    • Commonly associated facial features include broadened forehead, pointed chin, and elongated nose with bulbous tip.
    • Characteristic facial features may not be obvious during infancy but may become more apparent as the child ages.
  • Ophthalmologic
    • Ocular abnormalities are common.8 The most frequent ophthalmologic finding is a posterior embryotoxon, which was observed in more than 75% of patients in one large series conducted by Emerick et al.9
    • Some of these patients may also have the Axenfeld anomaly (ie, iris attachment to Descemet membrane).
    • Other findings reported include retinitis pigmentosa, pupillary abnormalities, and anomalies of the optic disc.
  • Cardiovascular
  • Hepatic
    • Hepatic disease is a key feature of Alagille syndrome.
    • Most infants present with cholestatic jaundice.
    • Hepatosplenomegaly is common.
    • Elevations in serum bile acids often result in severe pruritus and xanthomas (hypercholesterolemia).
    • Fat-soluble vitamin deficiencies, including coagulopathies and rickets, are frequent.
  • Skeletal
    • Abnormalities of the vertebrae, ribs, and hands are frequently associated with Alagille syndrome.
    • Butterfly hemivertebrae were found in one half of the patients analyzed by Emerick et al in a large series of patients with Alagille syndrome.9
    • Other isolated anomalies include rib anomalies and shortening of the radius, ulna, and phalanges.
  • Neurologic
    • Mild developmental delay and mental retardation are reported in some children with Alagille syndrome.
    • If noted during the physical examination, diminished deep tendon reflexes should direct the clinician to exclude vitamin E deficiency.
  • Renal: Occult renal artery stenosis, lipoid nephrosis, or glomerulosclerosis may present with signs and symptoms of chronic hypertension.
  • Vascular: Vascular lesions have been recently described in 6% of the patients with confirmed Alagille syndrome who were followed by Kamath et al.11 These lesions included basilar artery aneurysms, internal carotid artery anomalies, middle cerebral artery aneurysm, Moyamoya disease and aortic aneurysms, coarctation of the aorta, and renal artery stenosis.

Causes

  • Alagille syndrome is an autosomal dominant mutation with variable expression localized to the JAG1 gene (20p12).
  • The JAG1 gene product functions as a ligand for the notch-1 receptor. In animal models, interactions between JAG1 ligand and notch-1 receptor play an important role in the determination of ultimate cell fate. Few patients, generally those with more severe phenotypes, have complete deletion of the JAG1 gene.

More on Alagille Syndrome

Overview: Alagille Syndrome
Differential Diagnoses & Workup: Alagille Syndrome
Treatment & Medication: Alagille Syndrome
Follow-up: Alagille Syndrome
Multimedia: Alagille Syndrome
References
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References

  1. Krantz ID, Piccoli DA, Spinner NB. Alagille syndrome. J Med Genet. Feb 1997;34(2):152-7. [Medline].

  2. Watson GH, Miller V. Arteriohepatic dysplasia: familial pulmonary arterial stenosis with neonatal liver disease. Arch Dis Child. Jun 1973;48(6):459-66. [Medline].

  3. Alagille D, Odievre 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. Jan 1975;86(1):63-71. [Medline].

  4. McDaniell R, Warthen DM, Sanchez-Lara PA, et al. NOTCH2 mutations cause Alagille syndrome, a heterogeneous disorder of the notch signaling pathway. Am J Hum Genet. Jul 2006;79(1):169-73. [Medline].

  5. 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. Jul 1997;16(3):243-51. [Medline].

  6. Krantz ID, Colliton RP, Genin A, et al. Spectrum and frequency of jagged1 (JAG1) mutations in Alagille syndrome patients and their families. Am J Hum Genet. Jun 1998;62(6):1361-9. [Medline].

  7. Bucuvalas JC, Horn JA, Carlsson L, et al. Growth hormone insensitivity associated with elevated circulating growth hormone-binding protein in children with Alagille syndrome and short stature. J Clin Endocrinol Metab. Jun 1993;76(6):1477-82. [Medline].

  8. Hingorani M, Nischal KK, Davies A, et al. Ocular abnormalities in Alagille syndrome. Ophthalmology. Feb 1999;106(2):330-7. [Medline].

  9. Emerick KM, Rand EB, Goldmuntz E, et al. Features of Alagille syndrome in 92 patients: frequency and relation to prognosis. Hepatology. Mar 1999;29(3):822-9. [Medline].

  10. Lalani SR, Thakuria JV, Cox GF, Wang X, Bi W, Bray MS. 20p12.3 microdeletion predisposes to Wolff-Parkinson-White syndrome with variable neurocognitive deficits. J Med Genet. Mar 2009;46(3):168-75. [Medline].

  11. Kamath BM, Spinner NB, Emmerich KM, et al. Vascular anomalies in Alagille syndrome: a significant cause of morbidity and mortality. Circulation. 2004;110:1354-8. [Medline]. [Full Text].

  12. Cynamon HA, Andres JM, Iafrate RP. Rifampin relieves pruritus in children with cholestatic liver disease. Gastroenterology. Apr 1990;98(4):1013-6. [Medline].

  13. Kasahara M, Kiuchi T, Inomata Y, et al. Living-related liver transplantation for Alagille syndrome. Transplantation. Jun 27 2003;75(12):2147-50. [Medline].

  14. Whitington PF, Whitington GL. Partial external diversion of bile for the treatment of intractable pruritus associated with intrahepatic cholestasis. Gastroenterology. Jul 1988;95(1):130-6. [Medline].

  15. [Guideline] Murray KF, Carithers RL Jr. AASLD practice guidelines: Evaluation of the patient for liver transplantation. Hepatology. Jun 2005;41(6):1407-32. [Medline]. [Full Text].

  16. Bekassy AN, Garwicz S, Wiebe T, et al. Hepatocellular carcinoma associated with arteriohepatic dysplasia in a 4-year-old girl. Med Pediatr Oncol. 1992;20(1):78-83. [Medline].

  17. Danks DM, Campbell PE, Jack I, et al. Studies of the aetiology of neonatal hepatitis and biliary atresia. Arch Dis Child. May 1977;52(5):360-7. [Medline].

  18. Gottrand F, Clavey V, Fruchart JC, Farriaux JP. Lipoprotein pattern and plasma lecithin cholesterol acyl transferase activity in children with Alagille syndrome. Atherosclerosis. Jun 1995;115(2):233-41. [Medline].

  19. Hoffenberg EJ, Narkewicz MR, Sondheimer JM, et al. Outcome of syndromic paucity of interlobular bile ducts (Alagille syndrome) with onset of cholestasis in infancy. J Pediatr. Aug 1995;127(2):220-4. [Medline].

  20. Kay MH, Wyllie R, Steffen RM. Use of ursodeoxycholic acid in the treatment of arteriohepatic dysplasia. Clin Pediatr (Phila). Nov 1996;35(11):593-6. [Medline].

  21. Martin SR, Garel L, Alvarez F. Alagille's syndrome associated with cystic renal disease. Arch Dis Child. Mar 1996;74(3):232-5. [Medline].

  22. Miguet JP, Mavier P, Soussy CJ, Dhumeaux D. Induction of hepatic microsomal enzymes after brief administration of rifampicin in man. Gastroenterology. May 1977;72(5 Pt 1):924-6. [Medline].

  23. Oestreich AE, Sokol RJ, Suchy FJ, Heubi JE. Renal abnormalities in arteriohepatic dysplasia and nonsyndromic intrahepatic biliary hypoplasia. Ann Radiol (Paris). Feb-Mar 1983;26(2-3):203-9. [Medline].

  24. Quiros-Tejeira RE, Ament ME, Heyman MB, et al. Variable morbidity in alagille syndrome: a review of 43 cases. J Pediatr Gastroenterol Nutr. Oct 1999;29(4):431-7. [Medline].

  25. Rabinovitz M, Imperial JC, Schade RR, Van Thiel DH. Hepatocellular carcinoma in Alagille's syndrome: a family study. J Pediatr Gastroenterol Nutr. Jan 1989;8(1):26-30. [Medline].

  26. Russo PA, Ellis D, Hashida Y. Renal histopathology in Alagille's syndrome. Pediatr Pathol. 1987;7(5-6):557-68. [Medline].

  27. Shulman SA, Hyams JS, Gunta R. Arteriohepatic dysplasia (Alagille syndrome): extreme variability among affected family members. Am J Med Genet. Oct 1984;19(2):325-32. [Medline].

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Further Reading

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Keywords

Alagille syndrome, AS, Alagille's syndrome, Alagille-Watson syndrome, arteriohepatic dysplasia, syndromic bile duct paucity, pulmonary valvular stenosis, hypoplasia of the hepatic ducts, mental retardation, treatment, diagnosis

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Contributor Information and Disclosures

Author

Ann Scheimann, MD, MBA, Associate Professor, Department of Pediatrics, Section of Nutrition and Gastroenterology, Baylor College of Medicine and Johns Hopkins Medical Institution
Ann Scheimann, MD, MBA is a member of the following medical societies: North American Society for Pediatric Gastroenterology and Nutrition
Disclosure: Nothing to disclose.

Medical Editor

Robert Baldassano, MD, Director, Center for Pediatric Inflammatory Bowel Disease, Division of Gastroenterology and Nutrition, Associate Professor, Department of Pediatrics, The Children's Hospital of Philadelphia, University of Pennsylvania
Robert Baldassano, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American Gastroenterological Association, and North American Society for Pediatric Gastroenterology and Nutrition
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

CME Editor

Steven M Schwarz, MD, FAAP, FACN, AGAF, Professor of Pediatrics, Children's Hospital at Downstate, SUNY-Downstate Medical Center
Steven M Schwarz, MD, FAAP, FACN, AGAF is a member of the following medical societies: American Academy of Pediatrics, American College of Nutrition, American College of Physician Executives, American Gastroenterological Association, American Pediatric Society, Gastroenterology Research Group, New York Academy of Medicine, North American Society for Pediatric Gastroenterology and Nutrition, and Society for Pediatric Research
Disclosure: TAP Pharmaceuticals Honoraria Speaking and teaching; Curemark, LLC Consulting fee Board membership; Centocor, Inc. Grant/research funds Independent contractor

Chief Editor

Carmen Cuffari, MD, Associate Professor, Department of Pediatrics, Division of Gastroenterology/Nutrition, Johns Hopkins University School of Medicine
Carmen Cuffari, MD is a member of the following medical societies: American College of Gastroenterology, American Gastroenterological Association, North American Society for Pediatric Gastroenterology, Hepatology and Nutrition, and Royal College of Physicians and Surgeons of Canada
Disclosure: Nothing to disclose.

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