Alternative titles; symbols
SNOMEDCT: 32891000; ICD10CM: E80.6; ORPHA: 3111;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 12p12.2 | Hyperbilirubinemia, Rotor type, digenic | 237450 | Digenic recessive | 3 | SLCO1B3 | 605495 |
| 12p12.1 | Hyperbilirubinemia, Rotor type, digenic | 237450 | Digenic recessive | 3 | SLCO1B1 | 604843 |
A number sign (#) is used with this entry because Rotor type hyperbilirubinemia (HBLRR) is caused by digenic inheritance of homozygous mutations in the SLCO1B1 (604843) and SLCO1B3 (605495) genes, which are located near each other on chromosome 12p.
The Rotor type of hyperbilirubinemia is an autosomal recessive form of primary conjugated hyperbilirubinemia. It is similar to Dubin-Johnson syndrome (DJS; 237500) in that affected individuals develop mild jaundice not associated with hemolysis shortly after birth or in childhood. However, Rotor syndrome can be distinguished from DJS by a lack of hepatocyte pigment deposits, delayed plasma clearance of the unconjugated anionic dye bromsulfthalein, poor hepatic visualization on certain radiographic imaging studies, and prominent urinary excretion of coproporphyrin I (summary by van de Steeg et al., 2012).
Because of clinical similarities, the Rotor and Dubin-Johnson syndromes were initially considered to be the same entity. However, studies of urinary coproporphyrin excretion (Wolkoff et al., 1976) and sulfobromophthalein excretion (Wolpert et al., 1977) in the 2 disorders indicated that they were separate entities. Unlike Dubin-Johnson syndrome, Rotor syndrome shows no abnormal hepatic pigmentation and oral cholecystography is often normal. Total coproporphyrin excretion in the urine is markedly increased in Rotor syndrome. Dubin-Johnson patients excreted 88.9% as coproporphyrin I, whereas this value was 64.8% in Rotor homozygotes and 42.9% in Rotor heterozygotes. The standard errors of these values were such that the differences were highly significant (Wolkoff et al., 1976).
Three sibs from a first-cousin marriage were affected in the family reported by Pereira Lima et al. (1966), suggesting recessive inheritance.
Dollinger et al. (1967) observed a father and 3 of 5 children with what they considered to be Rotor syndrome; however, occult hemolysis was also present, which is not a feature of Rotor syndrome.
By homozygosity mapping of 8 families with Rotor syndrome, van de Steeg et al. (2012) found linkage to a single region on chromosome 12. Three distinct haplotypes were identified.
In affected members of 8 families with Rotor type hyperbilirubinemia, van de Steeg et al. (2012) identified 2 different homozygous mutations in 2 different genes: the SLCO1B1 gene (604843.0001-604843.0003) and the SLCO1B3 gene (605495.0001-605495.0003). Three of the families, who were Saudi Arabian, were homozygous for a 405-kb deletion on chromosome 12 encompassing exons 3 to 15 of SLCO1B3 (605495) and the whole of SLCO1B1, as well as homozygous for a splice site mutation in SLCO1B1 (604843.0002). Immunostaining of patient liver biopsies showed absence of detectable staining for both of these proteins. Segregation patterns in the families indicated that the disorder can only be caused by complete and simultaneous deficiencies of these 2 genes, which mediate uptake and clearance of conjugated bilirubin across the hepatic sinusoidal membranes into bile. Screening of 2,300 additional individuals identified 1 without jaundice who was heterozygous for a truncating mutation in SLCO1B1 and also homozygous for a deletion in SLCO1B3; this demonstrated that a single functional SLCO1B1 allele can prevent the disorder. Van de Steeg et al. (2012) suggested that individuals with Rotor syndrome may also be at increased risk for drug toxicity, since these proteins are involved in the clearance of drug conjugates.
Dollinger, M. R., Brandborg, L. L., Sartor, V. E., Bernstein, J. M. Chronic familial hyperbilirubinemia. Hepatic defects associated with occult hemolysis. Gastroenterology 52: 875-881, 1967. [PubMed: 6024890]
Pereira Lima, J. E., Utz, E., Roisenberg, I. Hereditary nonhemolytic conjugated hyperbilirubinemia without abnormal liver cell pigmentation. A family study. Am. J. Med. 40: 628-633, 1966.
Schiff, L., Billing, B. H., Oikawa, Y. Familial nonhemolytic jaundice with conjugated bilirubin in the serum: a case study. New Eng. J. Med. 260: 1315-1318, 1959. [PubMed: 13666961] [Full Text: https://doi.org/10.1056/NEJM195906252602604]
van de Steeg, E., Stranecky, V., Hartmannova, H., Noskova, L., Hrebicek, M., Wagenaar, E., van Esch, A., de Waart, D. R., Oude Elferink, R. P. J., Kenworthy, K. E., Sticova, E., al-Edreesi, M., Knisely, A. S., Kmoch, S., Jirsa, M., Schinkel, A. H. Complete OATP1B1 and OATP1B3 deficiency causes human Rotor syndrome by interrupting conjugated bilirubin reuptake into the liver. J. Clin. Invest. 122: 519-528, 2012. [PubMed: 22232210] [Full Text: https://doi.org/10.1172/JCI59526]
Wolkoff, A. W., Wolpert, E., Pascasio, F. N., Arias, I. M. Rotor's syndrome: a distinct inheritable pathophysiologic entity. Am. J. Med. 60: 173-179, 1976. [PubMed: 766621] [Full Text: https://doi.org/10.1016/0002-9343(76)90426-5]
Wolpert, E., Pascasio, F. M., Wolkoff, A. W., Arias, I. M. Abnormal sulfobromophthalein metabolism in Rotor's syndrome and obligate heterozygotes. New Eng. J. Med. 296: 1099-1101, 1977. [PubMed: 850521] [Full Text: https://doi.org/10.1056/NEJM197705122961907]