Crigler-Najjar Syndrome Clinical Presentation

  • Author: Praveen K Roy, MD, AGAF; Chief Editor: Julian Katz, MD   more...
 
Updated: Mar 2, 2012
 

History

Because of its autosomal recessive transmission, consanguinity is a risk factor for Crigler-Najjar syndrome, especially type 1 Crigler-Najjar syndrome.

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Physical

Persistent jaundice is present at or soon after birth in type 1 Crigler-Najjar syndrome. Jaundice may not manifest until later in infancy or childhood in type 2 Crigler-Najjar syndrome. Kernicterus is the most worrisome consequence of hyperbilirubinemia and occurs in virtually all patients with untreated type 1 Crigler-Najjar syndrome, especially in the first few days of life. Bilirubin encephalopathy is rare in patients with type 2 Crigler-Najjar syndrome, but it can be induced by factors such as infection, anesthesia, or drug use. Clinical manifestations of kernicterus are hypotonia, deafness, oculomotor palsy, lethargy, and, ultimately, death.

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Causes

Both type 1 and type 2 Crigler-Najjar syndrome are transmitted by autosomal recessive inheritance. Alterations in the coding sequence of the UGT1 gene result in absent or reduced UGT activity, with marked impairment of bilirubin conjugation. The UGT1 gene is located on 2q37. Several isoforms of UGT1 enzyme exist based on the variability in the amino-terminal region of the final protein. These differences are the result of alternative splicing among 10 (possibly more) different types of exon 1 at the 5' end of the UGT1 gene and constant exons 2-5 at the 3' end. Thus, the different UGT1 isoforms are distinguished according to the type of exon 1 they contain.

A report from the The Netherlands by Sneitz et al identified 4 novel UGT1A1 alleles.[1] The investigators noted the presence of 2 mutations in several unrelated patients; they believe this finding suggests 2 founder effects in The Netherlands. The study also demonstrated a link between 3 structural mutations and the UGT1A1 *28 promoter polymorphism (rs5719145insTA).[1]

In examining the functional activity of 10 missense mutants (3 that previously reported; 7 that were found in this study) and assessing their activity toward bilirubin and 8 other UGT1A1 substrates, it was revealed that 5 mutants had residual activity that varied, depending on the substrate, from nondetectable to 94% of wild-type UGT1A2 activity.[1]

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Contributor Information and Disclosures
Author

Praveen K Roy, MD, AGAF  Gastroenterologist, Ochsner Clinic Foundation; Adjunct Associate Research Scientist, Lovelace Respiratory Research Institute; Editor-in-Chief, The Internet Journal of Gasteroenterology; Editorial Board, Signal Transduction Insights; Editorial Board, The Internet Journal of Epidemiology; Editorial Board, Gastrointestinal Endoscopy Review Letter

Praveen K Roy, MD, AGAF is a member of the following medical societies: American College of Gastroenterology, American Gastroenterological Association, and American Society of Gastrointestinal Endoscopy

Disclosure: Nothing to disclose.

Coauthor(s)

Mohamed Othman, MD  Resident Physician, Department of Internal Medicine, University of New Mexico School of Medicine

Disclosure: Nothing to disclose.

Alessio Pigazzi, MD  PhD, Head, Minimally Invasive Surgery Program, Division of Surgery, Department of General Oncologic Surgery, City of Hope National Medical Center

Disclosure: Nothing to disclose.

Jack Bragg, DO  Associate Professor, Department of Clinical Medicine, University of Missouri School of Medicine

Jack Bragg, DO is a member of the following medical societies: American College of Osteopathic Internists and American Osteopathic Association

Disclosure: Nothing to disclose.

Gautam Dehadrai, MD  Department Chair, Section Chief, Department of Interventional Radiology, Norman Regional Hospital

Gautam Dehadrai, MD is a member of the following medical societies: American College of Radiology, Medical Council of India, and Radiological Society of North America

Disclosure: Nothing to disclose.

Showkat Bashir, MD  Assistant Professor, Department of Medicine, Division of Gastroenterology, George Washington University, Washington, DC

Showkat Bashir, MD is a member of the following medical societies: American College of Gastroenterology, American College of Physicians, American Gastroenterological Association, and American Medical Association

Disclosure: Nothing to disclose.

Specialty Editor Board

Tushar Patel, MB, ChB  Professor of Medicine, Ohio State University Medical Center

Tushar Patel, MB, ChB is a member of the following medical societies: American Association for the Study of Liver Diseases and American Gastroenterological Association

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD  Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

BS Anand, MD  Professor, Department of Internal Medicine, Division of Gastroenterology, Baylor College of Medicine

BS Anand, MD is a member of the following medical societies: American Association for the Study of Liver Diseases, American College of Gastroenterology, American Gastroenterological Association, and American Society for Gastrointestinal Endoscopy

Disclosure: Nothing to disclose.

Alex J Mechaber, MD, FACP  Senior Associate Dean for Undergraduate Medical Education, Associate Professor of Medicine, University of Miami Miller School of Medicine

Alex J Mechaber, MD, FACP is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians-American Society of Internal Medicine, and Society of General Internal Medicine

Disclosure: Nothing to disclose.

Chief Editor

Julian Katz, MD  Clinical Professor of Medicine, Drexel University College of Medicine

Julian Katz, MD is a member of the following medical societies: American College of Gastroenterology, American College of Physicians, American Gastroenterological Association, American Geriatrics Society, American Medical Association, American Society for Gastrointestinal Endoscopy, American Society of Law, Medicine & Ethics, American Trauma Society, Association of American Medical Colleges, and Physicians for Social Responsibility

Disclosure: Nothing to disclose.

References

  1. Sneitz N, Bakker CT, de Knegt RJ, et al. Crigler-Najjar syndrome in The Netherlands: identification of four novel UGT1A1 alleles, genotype-phenotype correlation, and functional analysis of 10 missense mutants. Hum Mutat. Jan 2010;31(1):52-9. [Medline].

  2. Miranda PS, Bosma PJ. Towards liver-directed gene therapy for Crigler-Najjar syndrome. Curr Gene Ther. Apr 2009;9(2):72-82. [Medline].

  3. Birraux J, Menzel O, Wildhaber B, et al. A step toward liver gene therapy: efficient correction of the genetic defect of hepatocytes isolated from a patient with Crigler-Najjar syndrome type 1 with lentiviral vectors. Transplantation. Apr 15 2009;87(7):1006-12. [Medline].

  4. Lysy PA, Najimi M, Stephenne X, et al. Liver cell transplantation for Crigler-Najjar syndrome type I: update and perspectives. World J Gastroenterol. Jun 14 2008;14(22):3464-70. [Medline]. [Full Text].

  5. Ozcay F, Alehan F, Sevmis S, et al. Living related liver transplantation in Crigler-Najjar syndrome type 1. Transplant Proc. Sep 2009;41(7):2875-7. [Medline].

  6. Arias IM, Gartner LM, Cohen M. Chronic nonhemolytic unconjugated hyperbilirubinemia with glucuronyl transferase deficiency. Clinical, biochemical, pharmacologic and genetic evidence for heterogeneity. Am J Med. Sep 1969;47(3):395-409. [Medline].

  7. Costa E. Hematologically important mutations: bilirubin UDP-glucuronosyltransferase gene mutations in Gilbert and Crigler-Najjar syndromes. Blood Cells Mol Dis. Jan-Feb 2006;36(1):77-80. [Medline].

  8. Gupta R, Parashar Y. Crigler-Najjar syndrome type II. Indian J Pediatr. Nov 2004;71(11):1043. [Medline].

  9. Hafkamp AM, Nelisse-Haak R, Sinaasappel M, Oude Elferink RP, Verkade HJ. Orlistat treatment of unconjugated hyperbilirubinemia in Crigler-Najjar disease: a randomized controlled trial. Pediatr Res. Dec 2007;62(6):725-30. [Medline].

  10. Jansen PL. Diagnosis and management of Crigler-Najjar syndrome. Eur J Pediatr. Dec 1999;158 Suppl 2:S89-94. [Medline].

  11. Jansen PL. Genetic diseases of bilirubin metabolism: the inherited unconjugated hyperbilirubinemias. J Hepatol. Sep 1996;25(3):398-404. [Medline].

  12. Lucey JF, Suresh GK, Kappas A. Crigler-Najjar syndrome, 1952-2000: learning from parents and patients about a very rare disease and using the internet to recruit patients for studies. Pediatrics. May 2000;105(5):1152-3. [Medline].

  13. Nowicki MJ, Poley JR. The hereditary hyperbilirubinaemias. Baillieres Clin Gastroenterol. Jun 1998;12(2):355-67. [Medline].

  14. Owens IS, Basu NK, Banerjee R. UDP-glucuronosyltransferases: gene structures of UGT1 and UGT2 families. Methods Enzymol. 2005;400:1-22.

  15. Petit FM, Gajdos V, Francoual J. Allelic heterogeneity of Crigler-Najjar type I syndrome: a study of 24 cases. Clin Genet. Dec 2004;66(6):571-2.

  16. Robards C, Brull SJ. The anesthetic implications of Crigler-Najjar syndrome. Anesth Analg. Feb 2007;104(2):435-6. [Medline].

  17. Sampietro M, Iolascon A. Molecular pathology of Crigler-Najjar type I and II and Gilbert's syndromes. Haematologica. Feb 1999;84(2):150-7. [Medline].

  18. Servedio V, d'Apolito M, Maiorano N, et al. Spectrum of UGT1A1 mutations in Crigler-Najjar (CN) syndrome patients: identification of twelve novel alleles and genotype-phenotype correlation. Hum Mutat. Mar 2005;25(3):325. [Medline].

  19. Shevell MI, Majnemer A, Schiff D. Neurologic perspectives of Crigler-Najjar syndrome type I. J Child Neurol. Jun 1998;13(6):265-9. [Medline].

  20. Sleisenger MH, Fordtran JS, eds. Gastrointestinal Diseases: Pathophysiology, Diagnosis, Management. 5th ed. Philadelphia, Pa: WB Saunders Co; 1993:Chapter 85.

  21. Takeuchi K, Kobayashi Y, Tamaki S. Genetic polymorphisms of bilirubin uridine diphosphate-glucuronosyltransferase gene in Japanese patients with Crigler-Najjar syndrome or Gilbert's syndrome as well as in healthy Japanese subjects. J Gastroenterol Hepatol. Sep 2004;19(9):1023-8.

  22. Zmetakova I, Ferak V, Minarik G, et al. Identification of the deletions in the UGT1A1 gene of the patients with Crigler-Najjar syndrome type I from Slovakia. Gen Physiol Biophys. Dec 2007;26(4):306-10. [Medline].

 
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