Alagille Syndrome Clinical Presentation

  • Author: Ann Scheimann, MD, MBA; Chief Editor: Carmen Cuffari, MD   more...
 
Updated: Feb 7, 2012
 

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.[8] 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.[9] 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.[10]
    • 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.[10]
    • 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. Data from one study show that renal involvement was present in 73 (39%) of 187 of the evaluable pediatric Alagille syndrome patients studied, with renal dysplasia being the most common anomaly. The researchers suggested that renal involvement be considered a defining criterion for Alagille syndrome.[12]
  • Vascular: Vascular lesions have been recently described in 6% of the patients with confirmed Alagille syndrome who were followed by Kamath et al.[13] 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.
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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.

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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.

Specialty Editor Board

Robert Baldassano, MD  Director, Center for Pediatric Inflammatory Bowel Disease, Children's Hospital of Philadelphia; Professor, Department of Pediatrics, Division of Gastroenterology and Nutrition, University of Pennsylvania School of Medicine

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: Abbott, Inc Consulting fee Consulting

Mary L Windle, PharmD  Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Steven M Schwarz, MD, FAAP, FACN, AGAF  Professor of Pediatrics, Children's Hospital at Downstate, State University of New York 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: Curemark, LLC Consulting fee Board membership; Centocor, Inc. Grant/research funds Independent contractor; Johnson & Johnson, 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.

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. Sparks EE, Huppert KA, Brown MA, Washington MK, Huppert SS. Notch Signaling Regulates Formation of the Three-Dimensional Architecture of Intrahepatic Bile Ducts in Mice. Hepatology. 2009;[Medline].

  8. 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].

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

  10. 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].

  11. 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].

  12. Kamath BM, Podkameni G, Hutchinson AL, et al. Renal anomalies in Alagille syndrome: A disease-defining feature. Am J Med Genet A. Nov 21 2011;[Medline].

  13. 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].

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

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

  16. 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].

  17. [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].

  18. Arnon R, Annunziato R, Miloh T, et al. Orthotopic liver transplantation for children with Alagille syndrome. Pediatr Transplant. Jan 11 2010;[Medline].

  19. 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].

  20. 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].

  21. 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].

  22. 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].

  23. 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].

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

  25. 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].

  26. 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].

  27. 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].

  28. 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].

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

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