DiagnosisClinical Diagnosis Rotor syndrome is characterized by mild jaundice which may be intermittent. Except for conjunctival icterus in some affected individuals, physical examination is normal.TestingLaboratory findings in Rotor syndrome are summarized in Table 1.Conjugated hyperbilirubinemia is the hallmark of the disorder. Serum total bilirubin concentration is usually between 2 and 5 mg/dL, but can be higher. Conjugated bilirubin usually exceeds 50% of total bilirubin. Table 1. Laboratory Findings in Rotor SyndromeView in own windowFindingRotor SyndromeNormalSerum bilirubinTotal 2-5 mg/dL ^{10.3-1.0 mg/dL 2Conjugated: total>50%<20%UrineBilirubinPresentNot detectedCoproporphyrins↑ 2.5-5x normal 3HemolysisNoneNoneDisappearance of plasma anionic compounds 4DelayedRapidCholescintigraphySee footnote 5NormalLiverEnzymesNormalNormalAppearanceNormalNormalHistologyNormal 6NormalProtein expression Absence of OATP1B1 and OATP1B3 7Normal1. Rarely may be up to 5-10 mg/dL [Author personal observation] or up to 20 mg/dL [Chowdhury et al 2001]2. For total and direct bilirubin in persons over age one year. Note: Although normal levels of total and direct bilirubin may be higher in the neonatal period and infancy, Rotor syndrome is not usually diagnosed in this age group. 3. Coproporphyrinuria is frequently observed in those with parenchymal liver diseases, and thus is not specific to Rotor syndrome.4. Includes bromosulfophthalein and indocyanin green5. Radiotracers (99mTc-HIDA/99mTc-N [2,6-dimethylphenyl-carbamoylmethyl] iminodiacetic acid, 99mTc-DISIDA/disofenin, 99mTc- BrIDA/mebrofenin) are taken up slowly by the liver and the liver is scarcely visualized; however, there is persistent visualization of the cardiac blood pool and prominent excretion by the kidneys.6. Note that suspicion of hereditary jaundice is not an indication for liver biopsy.7. Immunohistologic staining does not detect OATP1B1 and OATP1B3 at the sinusoidal membrane of hepatocytes. Note: Expression of MRP2, frequently absent in Dubin-Johnson syndrome (see Differential Diagnosis), is normal [Hrebícek et al 2007]. Molecular Genetic Testing Genes. SLCO1B1 and SLCO1B3 are the two genes in which biallelic inactivating mutations must be present to cause Rotor syndrome [van de Steeg et al 2012]. Of note, the Rotor syndrome locus comprises both genes which lie very close together on the same chromosome. (See Table A for chromosome locus and protein name for these genes.) Testing. The following are the findings of molecular genetic studies of 11 affected individuals from eight unrelated consanguineous families [van de Steeg et al 2012]. All affected individuals were homozygous for biallelic inactivating mutations in both SLCO1B1 and SLCO1B3:A biallelic whole-gene deletion spanning both SLCO1B1 and SLCO1B3 was present in four families.A biallelic nonsense mutation in SLCO1B1 and a biallelic deletion of exon 12 in SLCO1B3 were present in three families.A nonsense mutation in SLCO1B1A and a biallelic splice site mutation in SLCO1B3 were present in one family.The data indicate that these or other large deletions are likely present in the homozygous state in persons with Rotor syndrome. Detection and characterization of exonic and whole-gene deletions in homozygotes is generally easier than in compound heterozygotes (i.e., the expected finding in offspring of non-related parents).Table 2. Summary of Molecular Genetic Testing Used in Rotor SyndromeView in own windowGene SymbolsProportion of Rotor Syndrome Attributed to Mutations in This GeneTest MethodMutations DetectedTest AvailabilitySLCO1B1 8/8 1 are doubly homozygous for inactivating mutations in both genesSequence analysisSequence variants 2Research onlyDeletion / duplication analysis 3Exonic or whole-gene deletionsSLCO1B3Sequence analysisSequence variants 2Deletion / duplication analysis 3Exonic or whole-gene deletions1. Van de Steeg et al [2012]2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.3. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).Testing Strategy To confirm/establish the diagnosis in a probandTotal and direct serum bilirubin concentrationTesting for presence of bilirubin in the urineTesting for hemolysis * ALT, AST, ALP, and γ-GT activity *Cholescintigraphy Total urinary porphyrins * Tests for hemolysis and measurement of ALT, AST, ALP, and γ-GT activity are needed to evaluate for hemolytic anemia and hepatobiliary diseases that are considered in the differential diagnosis of Rotor syndrome. Note: The liver is histologically normal in persons with Rotor syndrome; therefore, suspicion of hereditary jaundice is not an indication for liver biopsy.Tests not generally available:Urinary porphyrin fractionationImmunohistologic study for OATP1B1 and OATP1B3 in archival liver biopsy specimenMolecular genetic testing of SLCO1B1 and SLCO1B3 Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.Note: Carriers are heterozygotes for this disorder and are not at risk of developing the disorder.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this GeneReview are known to be associated with mutations in SLCO1B1 and SLCO1B3. Of note, sequence variants that predict an amino acid change in SLCO1B1 or SLCO1B3 resulting in reduced activity of the encoded transporters have been associated with altered sensitivity to some drugs.}

Natural History The only clinical feature of Rotor syndrome is mild jaundice due to conjugated and unconjugated hyperbilirubinemia that usually begins shortly after birth or in childhood. Jaundice may be intermittent. Conjunctival icterus may be the only clinical manifestation.

Genotype-Phenotype Correlations Hyperbilirubinemia develops only in persons with biallelic inactivating mutations in both SLCO1B1 and SLCO1B3 [van de Steeg et al 2012]. Presence of at least one wildtype (functional) allele of either SLCO1B1 or SLCO1B3 prevents Rotor-type hyperbilirubinemia. A combination of a mild mutation in one allele of either SLCO1B1 or SLCO1B3 with deleterious mutations affecting the remaining three alleles has not been documented.

Differential DiagnosisTable 3. Hyperbilirubinemia: OMIM Phenotypic SeriesView in own windowPhenotypePhenotype
MIM NumberGene/LocusGene/Locus
MIM NumberCrigler-Najjar syndrome, type I 218800 UGT1A1, UGT1, GNT1, BILIQTL1 191740 Crigler-Najjar syndrome, type II 606785 UGT1A1, UGT1, GNT1, BILIQTL1 191740 Dubin-Johnson syndrome 237500 ABCC2, CMOAT 601107 Gilbert syndrome 143500 UGT1A1, UGT1, GNT1, BILIQTL1 191740 Hyperbilirubinemia, familial transient neonatal 237900 UGT1A1, UGT1, GNT1, BILIQTL1 191740 Hyperbilirubinemia, Rotor type, digenic 237450 SLCO1B3, OATP8, OATP1B3, SLC21A8, HBLRR 605495 Hyperbilirubinemia, Rotor type, digenic 237450 SLCO1B1, LST1, OATP2, OATPC, OATP1B1, HBLRR 604843 Dubin-Johnson syndrome (DJS) (OMIM 237500), an autosomal recessive disorder of secretion of conjugated bilirubin into bile, is more common than Rotor syndrome. The findings in DJS are summarized in Table 4. In addition to jaundice, abdominal pain and hepatomegaly may be present in some persons with DJS. Table 4. Comparison of Findings in Dubin-Johnson Syndrome and Rotor SyndromeView in own windowFindingRotor SyndromeDubin-Johnson SyndromeNormalSerum bilirubinTotal 2-5 mg/dL ^{12-5 mg/dL 20.3-1.0 mg/dL 3Conjugated: total>50% >50% <20%UrineBilirubinPresent; urine may be darkPresent; urine may be darkNot detectedPorphyrinsTotal porphyrin output ↑; coproporphyrin ↑2.5-5x normalTotal porphyrin output normal 4<200 μg/24h 5HemolysisNoneNoneNoneDisappearance of plasma anionic compounds 6Severely delayedDelayedRapidCholescintigraphySee footnote 7See footnote 8NormalLiverEnzymes 9NormalNormalNormalAppearanceNormalDark 10NormalHistologyNormalSee footnote 11NormalProtein expressionAbsence of OATP1B1, OATP1B3 12, 13Absence of MRP2 15, 16Normal1. Rarely may be up to 5-10 mg/dL [Author, personal observation] or up to 20 mg/dL [Chowdhury et al 2001].2. May be higher3. For total and direct bilirubin in persons over age one year. Note: Although normal levels of total and direct bilirubin may be higher in the neonatal period and infancy, Rotor syndrome is not usually diagnosed in this age group. 4. Total urinary porphyrin output is normal; however, predominance of coproporphyrin isomer I among urinary porphyrin species is observed on chromatography.5. Total urinary porphyrin output6. Includes bromosulfophthalein, indocyanin green, and cholescintigraphy radiotracers (99mTc-HIDA/99mTc-N [2,6-dimethylphenyl-carbamoylmethyl] iminodiacetic acid, 99mTc-DISIDA/disofenin, 99mTc- BrIDA/mebrofenin). Note: In the Dubin-Johnson syndrome, bromosulfophthalein conjugates reappear in the blood after administration of unconjugated BSP; this is not the case in the Rotor syndrome.7. Scarcely visualized on cholescintigraphy, with slow liver uptake, persistent visualization of the cardiac blood pool, and prominent kidney excretion8. Visualization of the liver is normal or somewhat delayed but filling of the gallbladder is absent or delayed.9. Serum ALT, AST, ALP, and γ-GT activity10. The liver is macroscopically dark (sometimes black).11. Liver histology is characterized by accumulation of dark melanin-like pigment in lysosomes of hepatocytes. The pigment is PAS- and Masson–Fontana-reactive; however, in contrast to melanin it does not reduce neutral silver ammonium solution. Autofluorescence is another characteristic feature of the pigment. The pigment may be almost absent in infancy and in persons recovering from acute liver injury. Liver architecture is otherwise normal. 12. Immunohistologic staining does not detect OATP1B1 and OATP1B3 at the sinusoidal membrane of hepatocytes. Note: Expression of MRP2, which is absent in Dubin-Johnson syndrome , is normal [Hrebícek et al 2007].13. Expression of MRP2 in Rotor syndrome is unremarkable [Hrebícek et al 2007].14. Absence of multidrug resistance-associated protein 2 (MRP2) from the canalicular membrane of hepatocytes, observed in most but not all cases of DJS, is the consequence of mutations in ABCC2. ABCC2 encodes MRP2, which serves as the canalicular export pump for conjugated bilirubin and numerous other anionic compounds. 15. The older name of MRP2 (OMIM 601107) is cMOAT – canalicular multispecific organic anion transporter. Immunohistologic detection of MRP2 can be performed in archival paraffin embedded liver specimens. Hepatic storage disease (conjugated hyperbilirubinemia type III, OMIM 237550) was described as a third form of conjugated hyperbilirubinemia presumably distinct from either Rotor syndrome or Dubin-Johnson syndrome. Although a primary defect in hepatic uptake or storage of bilirubin is postulated, mutations in specific gene(s) responsible for this disorder have not been identified. Based on the phenotype, it is possible that hepatic storage disease is fundamentally similar to Rotor syndrome.The plasma disappearance rate and hepatic transport maximum for bromosulfophthalein, dibromosulfophthalein, rose bengal, and indocyanin green are decreased, but the most striking feature is marked reduction in storage of the dye by the liver. Bilirubin UDP-glucuronyltransferase activity, plasma bile acid concentrations, and conventional liver function test results are normal. Cholestatic liver diseases and/or bile duct obstruction should be suspected whenever hyperbilirubinemia is accompanied by clinical signs other than jaundice and by elevation of serum activity of ALT, AST, ALP, or γ-GT. The same holds true for any abnormal findings in the gallbladder and the biliary tree obtained by imaging and/or endoscopy techniques. Hemolytic jaundice is characterized by predominantly unconjugated hyperbilirubinemia and signs of increased hemolysis.Gilbert syndrome (OMIM 143500) is an autosomal recessive disorder of bilirubin metabolism caused by decreased rate of bilirubin conjugation catalyzed by UGT1A1. The decreased activity of UGT1A1 is caused by either the promoter TATA repeat variation A(TA)₇TAA (normal A(TA)₆TAA, which is often combined with the promoter SNP c.-3279T>G) or by missense mutations in the coding region of UGT1A1, which are frequent in the Japanese population but rare in Europeans. Hyperbilirubinemia is predominantly unconjugated, with conjugated bilirubin less than 20% of total serum bilirubin. Gilbert syndrome is the most frequently occurring form of hereditary jaundice, affecting about 5%-10% of all Europeans. Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).}

ManagementEvaluations Following Initial Diagnosis In most cases an individual diagnosed with Rotor syndrome is the child of a consanguineous couple. Thus, the diagnosis of Rotor syndrome may coincidentally identify such consanguinity. In some centers, this may be an indication for medical genetics consultation and/or genetic counseling. Treatment of ManifestationsNo treatment is required.Agents/Circumstances to AvoidNo adverse drug effects have been documented in Rotor syndrome; however, the absence of the hepatic proteins OATP1B1 and OATP1B3 may have serious consequences for liver uptake and toxicity of numerous commonly used drugs and/or their metabolites which enter the liver via either of the two OATP1B transporters. A list of drugs that enter the liver mainly via OATP1B1 and whose pharmacokinetics are known to be influenced by genetic variability in SLCO1B1 has been published [Niemi et al 2011]. Some of these drugs are also taken up by OATP1B3 [Shitara 2011]. The list includes:Statins – simvastatin, atorvastatin, pravastatin, puitavastatin, rosuvastatin, fluvastatinEzetimibeAnticancer drugs - methotrexate and irinotecanSartans – olmesartan and valsartanRifampicinMycophenolic acidTorsemideThiazolidine diones – pioglitazone and rosiglitazoneGlinides – nateglinide and repaglinideLopinavirFexofenadineEvaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Pregnancy Management No special pregnancy management issues from the perspective of an affected mother and/or from the perspective of an affected fetus are known. Of note, during pregnancy the hyperbilirubinemia of Rotor syndrome may complicate the diagnosis and management of liver disease related to pregnancy (e.g., intrahepatic cholestasis of pregnancy) and liver disease not related to pregnancy. Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Rotor Syndrome: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameHGMDSLCO1B112p12​.2-p12.1Solute carrier organic anion transporter family member 1B1SLCO1B1SLCO1B312p12​.2Solute carrier organic anion transporter family member 1B3SLCO1B3Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Rotor Syndrome (View All in OMIM) View in own window 237450HYPERBILIRUBINEMIA, ROTOR TYPE; HBLRR 604843SOLUTE CARRIER ORGANIC ANION TRANSPORTER FAMILY, MEMBER 1B1; SLCO1B1 605495SOLUTE CARRIER ORGANIC ANION TRANSPORTER FAMILY, MEMBER 1B3; SLCO1B3Molecular Genetic Pathogenesis A substantial fraction of bilirubin conjugated in hepatocytes is normally secreted back into the blood by the action of MRP3 (OMIM 604323), a homolog of MRP2 expressed at the sinusoidal membrane, and subsequently reabsorbed in downstream hepatocytes by OATP1B1 and OATP1B3. Another fraction, probably a small one, of conjugated bilirubin cleared from portal blood may originate from bilirubin conjugation in splanchnic organs. In Rotor syndrome, liver histology is normal; however, expression of OATP1B1 and OATP1B3 is completely absent. The functional consequence of this is that liver uptake of bilirubin mono- and diglucuronides is hampered, causing increased plasma bilirubin-glucuronide levels and jaundice. Deficiency of OATP1B1 and OATP1B3 also explains the poor uptake by the liver of unconjugated bilirubin and anionic dyes such as bromosulfophthalein, indocyanin green, rose bengal, and cholescintigraphy radiotracers (^99mTc-HIDA and related compounds). It also supports the earlier observations that in Rotor syndrome conjugated bromosulfophthalein does not appear in the blood after intravenous administration of its unconjugated precursor. Reduced hepatic (re-)uptake of coproporphyrin isomers probably underlies the increased urinary excretion of coproporphyrins.SLCO1B1Normal allelic variants. SLCO1B1 comprises one untranslated and 14 protein-coding exons. The only transcript is 2.8 kb long.Pathologic allelic variants. See van de Steeg et al [2012].Normal gene product. Organic anion-transporting polypeptide OATP1B1 is a 691 amino-acid-long protein containing 12 plasma membrane-spanning domains. The protein is expressed in liver cells and mediates sodium-independent uptake of diverse endogenous and exogenous compounds.Abnormal gene product. Rotor syndrome is caused by simultaneous absence of both SLCO1B1 and SLCO1B3 gene products. No abnormal SLCO1B1 gene product (non-functional protein) is known to be associated with Rotor syndrome; however, such a possibility cannot be ruled out.SLCO1B3Normal allelic variants. SLCO1B3 comprises one untranslated and 14 protein-coding exons. The only transcript is 2.8 kb long.Pathologic allelic variants. See van de Steeg et al [2012].Normal gene product. Organic anion transporting polypeptide OATP1B3, encoded by SLCO1B3, is a 702 amino-acid-long protein containing 12 plasma membrane-spanning domains. The protein is expressed in liver cells and mediates sodium-independent uptake of diverse endogenous and exogenous compounds.Abnormal gene product. Rotor syndrome is caused by simultaneous absence of both SLCO1B1 and SLCO1B3 gene products. No abnormal SLCO1B3 gene product (non-functional protein) is known to be associated with Rotor syndrome; however, such a possibility cannot be ruled out.