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Crigler-Najjar syndrome

MedGen UID:
1789261
•Concept ID:
C5551003
•
Disease or Syndrome
Synonyms: bilirubin UDP glucuronyl transferase deficiency; Bilirubin uridinediphosphate glucuronosyltransferase deficiency; bilirubin uridinediphosphate glucuronosyltransferase deficiency; Bilirubin-UGT deficiency; bilirubin-UGT deficiency; Crigler Najjar syndrome; Crigler-Najjar Syndrome; hereditary unconjugated hyperbilirubinemia; UGT deficiency
SNOMED CT: Crigler-Najjar syndrome (28259009)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
•Concept ID:
C0441748
•
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
Autosomal recessive inheritance (Orphanet)
 
Related gene: UGT1A1
 
Monarch Initiative: MONDO:0009044
Orphanet: ORPHA205

Definition

A rare hereditary disorder of bilirubin metabolism characterized by unconjugated hyperbilirubinemia due to a either a complete (type 1) or partial and inducible (type 2) hepatic deficit of UDP-glucuronosyltransferase 1A1 activity. The disorder manifests with neonatal jaundice with a risk of developing bilirubin encephalopathy. [from ORDO]

Professional guidelines

PubMed

Diagnostic criteria and contributors to Gilbert's syndrome.
Wagner KH, Shiels RG, Lang CA, Seyed Khoei N, Bulmer AC
Crit Rev Clin Lab Sci 2018 Mar;55(2):129-139. Epub 2018 Feb 1 doi: 10.1080/10408363.2018.1428526. PMID: 29390925
Genetic lesions of bilirubin uridine-diphosphoglucuronate glucuronosyltransferase (UGT1A1) causing Crigler-Najjar and Gilbert syndromes: correlation of genotype to phenotype.
Kadakol A, Ghosh SS, Sappal BS, Sharma G, Chowdhury JR, Chowdhury NR
Hum Mutat 2000 Oct;16(4):297-306. doi: 10.1002/1098-1004(200010)16:4<297::AID-HUMU2>3.0.CO;2-Z. PMID: 11013440
Diagnosis and management of Crigler-Najjar syndrome.
Jansen PL
Eur J Pediatr 1999 Dec;158 Suppl 2:S89-94. doi: 10.1007/pl00014330. PMID: 10603107

Recent clinical studies

Etiology

Disease burden of Crigler-Najjar syndrome: Systematic review and future perspectives.
Dhawan A, Lawlor MW, Mazariegos GV, McKiernan P, Squires JE, Strauss KA, Gupta D, James E, Prasad S
J Gastroenterol Hepatol 2020 Apr;35(4):530-543. Epub 2019 Oct 24 doi: 10.1111/jgh.14853. PMID: 31495946
Diagnostic criteria and contributors to Gilbert's syndrome.
Wagner KH, Shiels RG, Lang CA, Seyed Khoei N, Bulmer AC
Crit Rev Clin Lab Sci 2018 Mar;55(2):129-139. Epub 2018 Feb 1 doi: 10.1080/10408363.2018.1428526. PMID: 29390925
New insights in bilirubin metabolism and their clinical implications.
Sticova E, Jirsa M
World J Gastroenterol 2013 Oct 14;19(38):6398-407. doi: 10.3748/wjg.v19.i38.6398. PMID: 24151358Free PMC Article
Molecular pathology of Crigler-Najjar type I and II and Gilbert's syndromes.
Sampietro M, Iolascon A
Haematologica 1999 Feb;84(2):150-7. PMID: 10091414
The hereditary hyperbilirubinaemias.
Nowicki MJ, Poley JR
Baillieres Clin Gastroenterol 1998 Jun;12(2):355-67. doi: 10.1016/s0950-3528(98)90139-7. PMID: 9890077

Diagnosis

Diagnostic criteria and contributors to Gilbert's syndrome.
Wagner KH, Shiels RG, Lang CA, Seyed Khoei N, Bulmer AC
Crit Rev Clin Lab Sci 2018 Mar;55(2):129-139. Epub 2018 Feb 1 doi: 10.1080/10408363.2018.1428526. PMID: 29390925
Crigler-Najjar Syndrome: Current Perspectives and the Application of Clinical Genetics.
Ebrahimi A, Rahim F
Endocr Metab Immune Disord Drug Targets 2018;18(3):201-211. doi: 10.2174/1871530318666171213153130. PMID: 29237388
Inherited disorders of bilirubin clearance.
Memon N, Weinberger BI, Hegyi T, Aleksunes LM
Pediatr Res 2016 Mar;79(3):378-86. Epub 2015 Nov 23 doi: 10.1038/pr.2015.247. PMID: 26595536Free PMC Article
Hyperbilirubinemia syndromes (Gilbert-Meulengracht, Crigler-Najjar, Dubin-Johnson, and Rotor syndrome).
Strassburg CP
Best Pract Res Clin Gastroenterol 2010 Oct;24(5):555-71. doi: 10.1016/j.bpg.2010.07.007. PMID: 20955959
The hereditary hyperbilirubinaemias.
Nowicki MJ, Poley JR
Baillieres Clin Gastroenterol 1998 Jun;12(2):355-67. doi: 10.1016/s0950-3528(98)90139-7. PMID: 9890077

Therapy

Gene Therapy in Patients with the Crigler-Najjar Syndrome.
D'Antiga L, Beuers U, Ronzitti G, Brunetti-Pierri N, Baumann U, Di Giorgio A, Aronson S, Hubert A, Romano R, Junge N, Bosma P, Bortolussi G, Muro AF, Soumoudronga RF, Veron P, Collaud F, Knuchel-Legendre N, Labrune P, Mingozzi F
N Engl J Med 2023 Aug 17;389(7):620-631. doi: 10.1056/NEJMoa2214084. PMID: 37585628
What's next in gene therapy for Crigler-Najjar syndrome?
Aronson SJ, Ronzitti G, Bosma PJ
Expert Opin Biol Ther 2023 Feb;23(2):119-121. Epub 2022 Dec 29 doi: 10.1080/14712598.2022.2160237. PMID: 36579791
Hyperbilirubinemia syndromes (Gilbert-Meulengracht, Crigler-Najjar, Dubin-Johnson, and Rotor syndrome).
Strassburg CP
Best Pract Res Clin Gastroenterol 2010 Oct;24(5):555-71. doi: 10.1016/j.bpg.2010.07.007. PMID: 20955959
Towards liver-directed gene therapy for Crigler-Najjar syndrome.
Miranda PS, Bosma PJ
Curr Gene Ther 2009 Apr;9(2):72-82. doi: 10.2174/156652309787909508. PMID: 19355865
Hepatocyte transplantation.
Fox IJ, Chowdhury JR
Am J Transplant 2004;4 Suppl 6:7-13. doi: 10.1111/j.1600-6135.2004.0340.x. PMID: 14871269

Prognosis

Gene Therapy in Patients with the Crigler-Najjar Syndrome.
D'Antiga L, Beuers U, Ronzitti G, Brunetti-Pierri N, Baumann U, Di Giorgio A, Aronson S, Hubert A, Romano R, Junge N, Bosma P, Bortolussi G, Muro AF, Soumoudronga RF, Veron P, Collaud F, Knuchel-Legendre N, Labrune P, Mingozzi F
N Engl J Med 2023 Aug 17;389(7):620-631. doi: 10.1056/NEJMoa2214084. PMID: 37585628
Crigler-Najjar Syndrome Type 1: Pathophysiology, Natural History, and Therapeutic Frontier.
Strauss KA, Ahlfors CE, Soltys K, Mazareigos GV, Young M, Bowser LE, Fox MD, Squires JE, McKiernan P, Brigatti KW, Puffenberger EG, Carson VJ, Vreman HJ
Hepatology 2020 Jun;71(6):1923-1939. Epub 2020 Feb 5 doi: 10.1002/hep.30959. PMID: 31553814Free PMC Article
Assessment of UGT polymorphisms and neonatal jaundice.
Bartlett MG, Gourley GR
Semin Perinatol 2011 Jun;35(3):127-33. doi: 10.1053/j.semperi.2011.02.006. PMID: 21641485
Vigintiphobia revisited.
Watchko JF
Pediatrics 2005 Jun;115(6):1747-53. doi: 10.1542/peds.2004-1748. PMID: 15930239
Congenital nonhemolytic hyperbilirubinemias.
Cichoz-Lach H, Celiński K, Słomka M
Ann Univ Mariae Curie Sklodowska Med 2004;59(1):449-52. PMID: 16146029

Clinical prediction guides

Bilirubin metabolism and UDP-glucuronosyltransferase 1A1 variants in Asians: Pathogenic implications and therapeutic response.
Huang MJ, Chen PL, Huang CS
Kaohsiung J Med Sci 2022 Aug;38(8):729-738. Epub 2022 Aug 9 doi: 10.1002/kjm2.12579. PMID: 35942604
Crigler-Najjar Syndrome Type 1: Pathophysiology, Natural History, and Therapeutic Frontier.
Strauss KA, Ahlfors CE, Soltys K, Mazareigos GV, Young M, Bowser LE, Fox MD, Squires JE, McKiernan P, Brigatti KW, Puffenberger EG, Carson VJ, Vreman HJ
Hepatology 2020 Jun;71(6):1923-1939. Epub 2020 Feb 5 doi: 10.1002/hep.30959. PMID: 31553814Free PMC Article
Polymorphism of UDP-glucuronosyltransferase and drug metabolism.
Maruo Y, Iwai M, Mori A, Sato H, Takeuchi Y
Curr Drug Metab 2005 Apr;6(2):91-9. doi: 10.2174/1389200053586064. PMID: 15853761
Genetic lesions of bilirubin uridine-diphosphoglucuronate glucuronosyltransferase (UGT1A1) causing Crigler-Najjar and Gilbert syndromes: correlation of genotype to phenotype.
Kadakol A, Ghosh SS, Sappal BS, Sharma G, Chowdhury JR, Chowdhury NR
Hum Mutat 2000 Oct;16(4):297-306. doi: 10.1002/1098-1004(200010)16:4<297::AID-HUMU2>3.0.CO;2-Z. PMID: 11013440
Bilirubin metabolism and kernicterus.
Gourley GR
Adv Pediatr 1997;44:173-229. PMID: 9265971

Recent systematic reviews

Disease burden of Crigler-Najjar syndrome: Systematic review and future perspectives.
Dhawan A, Lawlor MW, Mazariegos GV, McKiernan P, Squires JE, Strauss KA, Gupta D, James E, Prasad S
J Gastroenterol Hepatol 2020 Apr;35(4):530-543. Epub 2019 Oct 24 doi: 10.1111/jgh.14853. PMID: 31495946
Pregnancy outcome in maternal Crigler-Najjar syndrome type II: a case report and systematic review of the literature.
Passuello V, Puhl AG, Wirth S, Steiner E, Skala C, Koelbl H, Kohlschmidt N
Fetal Diagn Ther 2009;26(3):121-6. Epub 2009 Sep 11 doi: 10.1159/000238122. PMID: 19752526

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