Alternative titles; symbols
SNOMEDCT: 68067009; ORPHA: 205, 79235;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 2q37.1 | Crigler-Najjar syndrome, type II | 606785 | Autosomal recessive | 3 | UGT1A1 | 191740 |
A number sign (#) is used with this entry because Crigler-Najjar syndrome type II is caused by homozygous or compound heterozygous mutation in the UDP-glucuronosyltransferase gene (UGT1A1; 191740) on chromosome 2q37.
Mutations in the same gene cause Gilbert syndrome (143500) and Crigler-Najjar syndrome type I (218800).
The hereditary hyperbilirubinemias (Wolkoff et al., 1983) include (1) those resulting in predominantly unconjugated hyperbilirubinemia: Gilbert or Arias syndrome, Crigler-Najjar syndrome type I, and Crigler-Najjar syndrome type II; and (2) those resulting in predominantly conjugated hyperbilirubinemia: Dubin-Johnson syndrome (237500), Rotor syndrome (237450), and several forms of intrahepatic cholestasis (147480, 211600, 214950, 243300). Detailed studies show that patients with Crigler-Najjar syndrome type II have reduced activity of bilirubin glucuronosyltransferase (Labrune et al., 1989, Seppen et al., 1994).
Type I and type II Crigler-Najjar syndrome are distinguished on the basis of the following clinical criteria: in type I, total serum bilirubin ranges from 20 to 45 mg/dL, whereas in type II, total serum bilirubin ranges from 6 to 20 mg/dL; in type II, phenobarbital treatment lowers serum bilirubin levels by more than 30%; and in type II, bilirubin glucuronides are present in bile. Type I patients do not respond to phenobarbital treatment and only traces of bilirubin glucuronides can be found in their bile. Analysis of liver tissue reveals residual activity of bilirubin-UGT activity in type II and absent activity in type I. There is considerable variability in type II, making it difficult to classify some cases. The enzyme produced from type I patients shows complete absence of activity and that in type II patients is reduced. Type II Crigler-Najjar syndrome is less severe than type I. Type I is associated with a reduced ability to glucuronidate bilirubin, with serum bilirubin levels ranging from 60 to 340 micromoles. Type I may be managed by phenobarbitone drug therapy, resulting in a reduction in serum bilirubin to 'safe' levels. Seppen et al. (1994) discriminated between types I and II by expressing mutant bilirubin-UGT in COS cells. Gilbert syndrome is distinguished by the lack of morbidity in patients and by a lower total serum bilirubin level, ranging from 1 to 6 mg/dL.
The inheritance pattern of Crigler-Najjar syndrome type II is generally considered to be autosomal recessive (Chowdhury et al., 2001). Hunter et al. (1973) described 3 families with apparently autosomal recessive inheritance, and Labrune et al. (1989) reported another. Consanguinity and the occurrence in brothers in the family reported by Gollan et al. (1975) supported recessive inheritance. Guldutuna et al. (1995) described Crigler-Najjar syndrome type II in a 34-year-old Turkish woman, the daughter of first-cousin parents. She and 3 of her 5 sibs (2 female, 1 male) had become jaundiced within the first days of life. The 4 jaundiced sibs had a total of 11 children, all unaffected. The mother, however, had the same disorder. The authors termed this pattern 'autosomal recessive with pseudodominance.' In the past, Powell et al. (1967) and Sleisenger et al. (1967), among others, reported autosomal dominant inheritance.
Moghrabi et al. (1993) described a point mutation in the UGT1 gene complex (191740.0005) in a 72-year-old man with Crigler-Najjar syndrome type II who was the product of a consanguineous marriage of Irish descent. The patient was one of the brothers reported by Gollan et al. (1975). Yamamoto et al. (1998) analyzed the coding and promoter regions of the UGT1 gene in 7 Japanese patients with Crigler-Najjar syndrome type II from 5 unrelated families. Double homozygous missense mutations in exons 1 and 5 were found in 5 patients from 3 of the families studied. A single homozygous missense mutation in exon 1 was detected in 1 patient. The final patient was homozygous for an insertion mutation (191740.0011) and heterozygous for a pro229-to-gln mutation (P229Q; 191740.0010). Both of these variants had previously been found in patients with Gilbert syndrome. The authors speculated that the phenotype of Crigler-Najjar syndrome type II in this patient was caused by a combination of the heterozygous missense and homozygous insertion mutations.
Kadakol et al. (2001) described 2 sisters with Crigler-Najjar syndrome type II. They identified a missense mutation in the UGT1A1 gene (191740.0021) in homozygous state, but also found homozygosity for the UGT1 promoter region mutation (191740.0011).
Petit et al. (2006) identified 15 different mutations, including 4 novel mutations, in the UGT1A1 gene among 13 patients with Crigler-Najjar syndrome type II.
Billing, B. H., Williams, R., Richards, T. G. Defects in hepatic transport of bilirubin in congenital hyperbilirubinaemia: an analysis of plasma bilirubin disappearance curves. Clin. Sci. 27: 245-257, 1964. [PubMed: 14220904]
Chowdhury, J. R., Wolkoff, A. W., Chowdhury, N. R., Arias, I. M. Hereditary jaundice and disorders of bilirubin metabolism.In: Scriver, C. R.; Beaudet, A. L.; Sly, W. S.; Valle, D. (eds.) : The Metabolic and Molecular Bases of Inherited Disease. Vol. II. (8th ed.) New York: McGraw-Hill (pub.) 2001. Pp. 3063-3101.
Gollan, J. L., Huang, S. N., Billing, B., Sherlock, S. Prolonged survival in three brothers with severe type 2 Crigler-Najjar syndrome: ultrastructural and metabolic studies. Gastroenterology 68: 1543-1555, 1975. [PubMed: 805737] [Full Text: https://linkinghub.elsevier.com/retrieve/pii/S0016508575001151]
Guldutuna, S., Langenbeck, U., Bock, K. W., Sieg, A., Leuschner, U. Crigler-Najjar syndrome type II: new observation of possible autosomal recessive inheritance. Digest. Dis. Sci. 40: 28-32, 1995. [PubMed: 7821116] [Full Text: https://dx.doi.org/10.1007/BF02063937]
Hunter, J. O., Thompson, R. P. H., Dunn, P. M., Williams, R. Inheritance of type 2 Crigler-Najjar hyperbilirubinaemia. Gut 14: 46-49, 1973. [PubMed: 4692254] [Full Text: https://dx.doi.org/10.1136/gut.14.1.46]
Kadakol, A., Sappal, B. S., Ghosh, S. S., Lowenheim, M., Chowdhury, A., Chowdhury, S., Santra, A., Arias, I. M., Chowdhury, J. R., Chowdhury, N. R. Interaction of coding region mutations and the Gilbert-type promoter abnormality of the UGT1A1 gene causes moderate degrees of unconjugated hyperbilirubinaemia and may lead to neonatal kernicterus. (Letter) J. Med. Genet. 38: 244-249, 2001. [PubMed: 11370628] [Full Text: https://dx.doi.org/10.1136/jmg.38.4.244]
Labrune, P., Myara, A., Hennion, C., Gout, J. P., Trivin, F., Odievre, M. Crigler-Najjar type II disease inheritance: a family study. J. Inherit. Metab. Dis. 12: 302-306, 1989. [PubMed: 2515370] [Full Text: https://dx.doi.org/10.1007/BF01799221]
Moghrabi, N., Clarke, D. J., Boxer, M., Burchell, B. Identification of an A-to-G missense mutation in exon 2 of the UGT1 gene complex that causes Crigler-Najjar syndrome type 2. Genomics 18: 171-173, 1993. [PubMed: 8276413] [Full Text: https://dx.doi.org/10.1006/geno.1993.1451]
Petit, F., Gajdos, V., Capel, L., Parisot, F., Myara, A., Francoual, J., Labrune, P. Crigler-Najjar type II syndrome may result from several types and combinations of mutations in the UGT1A1 gene. (Letter) Clin. Genet. 69: 525-527, 2006. [PubMed: 16712705] [Full Text: https://dx.doi.org/10.1111/j.1399-0004.2006.00616.x]
Powell, L. W., Hemingway, E., Billing, B. H., Sherlock, S. Idiopathic unconjugated hyperbilirubinemia (Gilbert's syndrome): a study of 42 families. New Eng. J. Med. 277: 1108-1112, 1967. [PubMed: 6054997] [Full Text: https://dx.doi.org/10.1056/NEJM196711232772102]
Seppen, J., Bosma, P. J., Goldhoorn, B. G., Bakker, C. T. M., Roy Chowdhury, J., Roy Chowdhury, N., Jansen, P. L. M., Oude Elferink, R. P. J. Discrimination between Crigler-Najjar type I and II by expression of mutant bilirubin uridine diphosphate-glucuronosyltransferase. J. Clin. Invest. 94: 2385-2391, 1994. [PubMed: 7989595] [Full Text: https://dx.doi.org/10.1172/JCI117604]
Sleisenger, M. H., Kahn, I., Barniville, H., Rubin, W., Ben-Ezzer, J., Arias, I. M. Nonhemolytic unconjugated hyperbilirubinemia with hepatic glucuronyl transferase deficiency: a genetic study in four generations. Trans. Assoc. Am. Phys. 80: 259-266, 1967. [PubMed: 6082246]
Wolkoff, A. W., Roy Chowdhury, J., Arias, I. M. Hereditary jaundice and disorders of bilirubin metabolism.In: Stanbury, J. B.; Wyngaarden, J. B.; Fredrickson, D. S.; Goldstein, J. L.; Brown, M. S. (eds.) : The Metabolic Basis of Inherited Disease. (5th ed.) New York: McGraw-Hill (pub.) 1983. Pp. 1385-1420.
Yamamoto, K., Soeda, Y., Kamisako, T., Hosaka, H., Fukano, M., Sato, H., Fujiyama, Y., Adachi, Y., Satoh, Y., Bamba, T. Analysis of bilirubin uridine 5-prime-diphosphate (UDP)-glucuronosyltransferase gene mutations in seven patients with Crigler-Najjar syndrome type II. J. Hum. Genet. 43: 111-114, 1998. [PubMed: 9621515] [Full Text: https://dx.doi.org/10.1007/s100380050050]