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Crigler-Najjar syndrome type 1(HBLRCN1)

MedGen UID:
41346
Concept ID:
C0010324
Disease or Syndrome
Synonyms: Crigler-Najjar Syndrome, Type I; HYPERBILIRUBINEMIA, CRIGLER-NAJJAR TYPE I
SNOMED CT: Crigler-Najjar syndrome, type I (8933000); Deficiency of glucuronosyltransferase (8933000); Glucuronyltransferase deficiency (8933000); UDP glucuronyl transferase deficiency (8933000); Crigler-Najjar type 1 (8933000); Bilirubin UDP glucuronyl transferase deficiency (8933000); Bilirubin glucuronosyltransferase deficiency (8933000); Crigler-Najjar syndrome type I (8933000)
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).
 
Gene (location): UGT1A1 (2q37.1)
 
Monarch Initiative: MONDO:0021020
OMIM®: 218800
Orphanet: ORPHA79234

Definition

Crigler-Najjar syndrome is a severe condition characterized by high levels of a toxic substance called bilirubin in the blood (hyperbilirubinemia). Bilirubin is produced when red blood cells are broken down. This substance is removed from the body only after it undergoes a chemical reaction in the liver, which converts the toxic form of bilirubin (called unconjugated bilirubin) to a nontoxic form called conjugated bilirubin. People with Crigler-Najjar syndrome have a buildup of unconjugated bilirubin in their blood (unconjugated hyperbilirubinemia).

Crigler-Najjar syndrome is divided into two types. Type 1 (CN1) is very severe, and affected individuals can die in childhood due to kernicterus, although with proper treatment, they may survive longer. Type 2 (CN2) is less severe. People with CN2 are less likely to develop kernicterus, and most affected individuals survive into adulthood.

Bilirubin has an orange-yellow tint, and hyperbilirubinemia causes yellowing of the skin and whites of the eyes (jaundice). In Crigler-Najjar syndrome, jaundice is apparent at birth or in infancy. Severe unconjugated hyperbilirubinemia can lead to a condition called kernicterus, which is a form of brain damage caused by the accumulation of unconjugated bilirubin in the brain and nerve tissues. Babies with kernicterus are often extremely tired (lethargic) and may have weak muscle tone (hypotonia). These babies may experience episodes of increased muscle tone (hypertonia) and arching of their backs. Kernicterus can lead to other neurological problems, including involuntary writhing movements of the body (choreoathetosis), hearing problems, or intellectual disability. [from MedlinePlus Genetics]

Clinical features

From HPO
Jaundice
MedGen UID:
43987
Concept ID:
C0022346
Sign or Symptom
Yellow pigmentation of the skin due to bilirubin, which in turn is the result of increased bilirubin concentration in the bloodstream.
Bilirubin encephalopathy
MedGen UID:
44018
Concept ID:
C0022610
Disease or Syndrome
Damage to cerebral nuclei caused in infants by highly increased levels of unconjugated bilirubin. The basal ganglia and brainstem nuclei could be shown to have a yellow staining historically in infants who died of kernicterus, that is, kernicterus is strictly speaking a pathological diagnosis. The presence of kernicterus may be inferred in infants with characteristic acute or chronic bilirubin-induced neurological dysfunction.
Encephalopathy
MedGen UID:
39314
Concept ID:
C0085584
Disease or Syndrome
Encephalopathy is a term that means brain disease, damage, or malfunction. In general, encephalopathy is manifested by an altered mental state.
Elevated circulating hepatic transaminase concentration
MedGen UID:
116013
Concept ID:
C0235996
Finding
Elevations of the levels of SGOT and SGPT in the serum. SGOT (serum glutamic oxaloacetic transaminase) and SGPT (serum glutamic pyruvic transaminase) are transaminases primarily found in the liver and heart and are released into the bloodstream as the result of liver or heart damage. SGOT and SGPT are used clinically mainly as markers of liver damage.
Unconjugated hyperbilirubinemia
MedGen UID:
82786
Concept ID:
C0268306
Disease or Syndrome
An increased amount of unconjugated (indirect) bilurubin in the blood.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
Follow this link to review classifications for Crigler-Najjar syndrome type 1 in Orphanet.

Professional guidelines

PubMed

Paulík A, Grim J, Filip S
Acta Medica (Hradec Kralove) 2012;55(4):153-9. doi: 10.14712/18059694.2015.39. PMID: 23631285
El-Shabrawi MH, Kamal NM
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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

Recent clinical studies

Etiology

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
Zubaida B, Cheema HA, Hashmi MA, Naeem M
Clin Biochem 2019 Jul;69:30-35. Epub 2019 May 27 doi: 10.1016/j.clinbiochem.2019.05.012. PMID: 31145902
Ozçay F, Alehan F, Sevmiş S, Karakayali H, Moray G, Torgay A, Arslan G, Haberal M
Transplant Proc 2009 Sep;41(7):2875-7. doi: 10.1016/j.transproceed.2009.07.025. PMID: 19765461
Suresh G, Lucey JF
Pediatrics 1997 Nov;100(5):E9. doi: 10.1542/peds.100.5.e9. PMID: 9347003
van der Veere CN, Sinaasappel M, McDonagh AF, Rosenthal P, Labrune P, Odièvre M, Fevery J, Otte JB, McClean P, Bürk G, Masakowski V, Sperl W, Mowat AP, Vergani GM, Heller K, Wilson JP, Shepherd R, Jansen PL
Hepatology 1996 Aug;24(2):311-5. doi: 10.1002/hep.510240205. PMID: 8690398

Diagnosis

El-Anwar N, El-Shabrawi M, Shahin OO, Abdel Kareem R, Salama AM, Baroudy S
Paediatr Int Child Health 2024 May;44(1):18-23. Epub 2024 Feb 9 doi: 10.1080/20469047.2024.2309727. PMID: 38334259
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
Zubaida B, Cheema HA, Hashmi MA, Naeem M
Clin Biochem 2019 Jul;69:30-35. Epub 2019 May 27 doi: 10.1016/j.clinbiochem.2019.05.012. PMID: 31145902
Khan S, Irfan M, Sher G, Zubaida B, Alvi MA, Yasinzai M, Naeem M
Ann Hum Genet 2013 Nov;77(6):482-7. Epub 2013 Aug 29 doi: 10.1111/ahg.12039. PMID: 23992562
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

Therapy

Apgar JF, Tang JP, Singh P, Balasubramanian N, Burke J, Hodges MR, Lasaro MA, Lin L, Millard BL, Moore K, Jun LS, Sobolov S, Wilkins AK, Gao X
CPT Pharmacometrics Syst Pharmacol 2018 Jun;7(6):404-412. Epub 2018 Apr 26 doi: 10.1002/psp4.12301. PMID: 29637732Free PMC Article
Akdur A, Kirnap M, Ayvazoglu Soy EH, Ozcay F, Moray G, Arslan G, Haberal M
Exp Clin Transplant 2017 Feb;15(Suppl 1):128-132. doi: 10.6002/ect.mesot2016.P11. PMID: 28260452
Ozçay F, Alehan F, Sevmiş S, Karakayali H, Moray G, Torgay A, Arslan G, Haberal M
Transplant Proc 2009 Sep;41(7):2875-7. doi: 10.1016/j.transproceed.2009.07.025. PMID: 19765461
Rela M, Muiesan P, Vilca-Melendez H, Dhawan A, Baker A, Mieli-Vergani G, Heaton ND
Ann Surg 1999 Apr;229(4):565-9. doi: 10.1097/00000658-199904000-00017. PMID: 10203091Free PMC Article
Whitington PF, Emond JC, Heffron T, Thistlethwaite JR
Lancet 1993 Sep 25;342(8874):779-80. doi: 10.1016/0140-6736(93)91543-u. PMID: 7690444

Prognosis

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
Burke MP, O'Donnell C, Baber Y
Forensic Sci Med Pathol 2017 Mar;13(1):82-85. Epub 2017 Jan 14 doi: 10.1007/s12024-016-9835-4. PMID: 28091982
Ozçay F, Alehan F, Sevmiş S, Karakayali H, Moray G, Torgay A, Arslan G, Haberal M
Transplant Proc 2009 Sep;41(7):2875-7. doi: 10.1016/j.transproceed.2009.07.025. PMID: 19765461
Schauer R, Stangl M, Lang T, Zimmermann A, Chouker A, Gerbes AL, Schildberg FW, Rau HG
J Pediatr Surg 2003 Aug;38(8):1227-31. doi: 10.1016/s0022-3468(03)00273-2. PMID: 12891498
Whitington PF, Emond JC, Heffron T, Thistlethwaite JR
Lancet 1993 Sep 25;342(8874):779-80. doi: 10.1016/0140-6736(93)91543-u. PMID: 7690444

Clinical prediction guides

El-Anwar N, El-Shabrawi M, Shahin OO, Abdel Kareem R, Salama AM, Baroudy S
Paediatr Int Child Health 2024 May;44(1):18-23. Epub 2024 Feb 9 doi: 10.1080/20469047.2024.2309727. PMID: 38334259
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
Apgar JF, Tang JP, Singh P, Balasubramanian N, Burke J, Hodges MR, Lasaro MA, Lin L, Millard BL, Moore K, Jun LS, Sobolov S, Wilkins AK, Gao X
CPT Pharmacometrics Syst Pharmacol 2018 Jun;7(6):404-412. Epub 2018 Apr 26 doi: 10.1002/psp4.12301. PMID: 29637732Free PMC Article
Dhawan A, Mitry RR, Hughes RD
J Inherit Metab Dis 2006 Apr-Jun;29(2-3):431-5. doi: 10.1007/s10545-006-0245-8. PMID: 16763914
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

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