Rotor Syndrome
Synonym: Rotor-Type Hyperbilirubinemia
Milan Jirsa, MD, PhD, AS Knisely, MD, Alfred Schinkel, PhD, and Stanislav Kmoch, PhD.
Author InformationInitial Posting: December 13, 2012.
Summary
Clinical characteristics.
Rotor syndrome is characterized by mild conjugated and unconjugated hyperbilirubinemia which usually begins shortly after birth or in childhood. Jaundice may be intermittent. Conjunctival icterus may be the only clinical manifestation.
Diagnosis/testing.
Predominantly conjugated hyperbilirubinemia is the hallmark of the disorder: serum total bilirubin concentration is usually between 2 and 5 mg/dL, but can be higher. Biallelic inactivating pathogenic variants in the closely linked genes SLCO1B1 and SLCO1B3 that result in complete functional deficiencies of both protein products (OATP1B1 and OATP1B3, respectively) must be present to cause Rotor syndrome.
Management.
Treatment of manifestations: No treatment required.
Agents/circumstances to avoid: Although no adverse drug effects have been documented in persons with Rotor syndrome, the absence of the hepatic proteins OATP1B1 and OATP1B3 may have serious consequences for liver uptake and, thus, toxicity of numerous commonly used drugs and/or their metabolites.
Other: Because most individuals with Rotor syndrome are born to consanguineous couples, the diagnosis of Rotor syndrome may coincidentally identify such consanguinity. In some centers, this may be an indication for clinical genetics consultation and/or genetic counseling.
Genetic counseling.
Rotor syndrome is inherited in an autosomal recessive manner. The parents of an affected child are obligate heterozygotes for a pathogenic variant in SLCO1B1 and a pathogenic variant in SLCO1B3 or obligate heterozygotes for a large deletion affecting the coding regions of both SLCO1B1 and SLCO1B3. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier of at least one pathogenic variant, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members and prenatal testing for pregnancies at increased risk are possible through laboratories offering either testing for the gene of interest or custom testing. Requests for prenatal testing for benign, clinically unimportant conditions such as Rotor syndrome are not expected to be common.
Diagnosis
Clinical Diagnosis
Rotor syndrome is characterized by mild jaundice which may be intermittent. Except for conjunctival icterus in some affected individuals, physical examination is normal.
Testing
Laboratory findings in Rotor syndrome are summarized in .
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 Syndrome
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| Finding | Rotor Syndrome | Normal |
|---|
| Serum bilirubin | Total | 2-5 mg/dL 1 | 0.3-1.0 mg/dL 2 |
| Conjugated: total | >50% | <20% |
| Urine | Bilirubin | Present | Not detected |
| Coproporphyrins | ↑ 2.5-5x normal 3 | |
| Hemolysis | None | None |
| Disappearance of plasma anionic compounds 4 | Delayed | Rapid |
| Cholescintigraphy | See footnote 5 | Normal |
| Liver | Enzymes | Normal | Normal |
| Appearance | Normal | Normal |
| Histology | Normal 6 | Normal |
| Protein expression | Absence of OATP1B1 and OATP1B3 7 | Normal |
- 1.
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 older than 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 green
- 5.
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 pathogenic variants 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.
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 pathogenic variants in both SLCO1B1 and SLCO1B3:
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 exon 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 Syndrome
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| Gene 1 | Proportion of Rotor Syndrome Attributed to Pathogenic Variants in This Gene | Test Method | Variants Detected 2 |
|---|
| SLCO1B1 | 8/8 3 are doubly homozygous for inactivating pathogenic variants in both genes | Sequence analysis 4 | Sequence variants |
| Deletion/duplication analysis 5 | Exon or whole-gene deletions |
| SLCO1B3 | Sequence analysis | Sequence variants 4 |
| Deletion/duplication analysis 5 | Exon or whole-gene deletions |
- 1.
- 2.
- 3.
- 4.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 5.
Testing Strategy
To confirm/establish the diagnosis in a proband
Total and direct serum bilirubin concentration
Testing for presence of bilirubin in the urine
Testing 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 fractionation
Immunohistologic study for OATP1B1 and OATP1B3 in archival liver biopsy specimen
Molecular genetic testing of SLCO1B1 and SLCO1B3
Carrier testing for at-risk relatives requires prior identification of the pathogenic variants 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 pathogenic variants in the family.
Clinical Characteristics
Clinical Description
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 pathogenic variants in both SLCO1B1 and SLCO1B3 [van de Steeg et al 2012]. Presence of at least one wild-type (functional) allele of either SLCO1B1 or SLCO1B3 prevents Rotor-type hyperbilirubinemia.
A combination of a mild variant in one allele of either SLCO1B1 or SLCO1B3 with deleterious variants affecting the remaining three alleles has not been documented.
Penetrance
Penetrance for this disorder is complete and is the same for males and females.
Prevalence
The prevalence of Rotor syndrome is unknown, but is very low (<1:1,000,000).
No information is available regarding specific populations in which the prevalence may be greater or less than expected.
Differential Diagnosis
See Hyperbilirubinemia: OMIM Phenotypic Series to view genes associated with this phenotype in OMIM.
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 . In addition to jaundice, abdominal pain and hepatomegaly may be present in some persons with DJS.
Table 3.
Comparison of Findings in Dubin-Johnson Syndrome and Rotor Syndrome
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| Finding | Rotor Syndrome | Dubin-Johnson Syndrome | Normal |
|---|
| Serum bilirubin | Total | 2-5 mg/dL 1 | 2-5 mg/dL 2 | 0.3-1.0 mg/dL 3 |
| Conjugated: total | >50% | >50% | <20% |
| Urine | Bilirubin | Present; urine may be dark | Present; urine may be dark | Not detected |
| Porphyrins | Total porphyrin output ↑; coproporphyrin ↑2.5-5x normal | Total porphyrin output normal 4 | <200 μg/24h 5 |
| Hemolysis | None | None | None |
| Disappearance of plasma anionic compounds 6 | Severely delayed | Delayed | Rapid |
| Cholescintigraphy | See footnote 7 | See footnote 8 | Normal |
| Liver | Enzymes 9 | Normal | Normal | Normal |
| Appearance | Normal | Dark 10 | Normal |
| Histology | Normal | See footnote 11 | Normal |
| Protein expression | Absence of OATP1B1, OATP1B3 12, 13 | Absence of MRP2 15, 16 | Normal |
- 1.
Rarely may be up to 5-10 mg/dL [Author, personal observation] or up to 20 mg/dL [Chowdhury et al 2001].
- 2.
- 3.
For total and direct bilirubin in persons older than 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 output
- 6.
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 excretion
- 8.
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 activity
- 10.
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.
- 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 pathogenic variants 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, variants 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 variants 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.
Management
Evaluations 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 clinical genetics consultation and/or genetic counseling.
Treatment of Manifestations
No treatment is required.
Agents/Circumstances to Avoid
No 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, fluvastatin
Ezetimibe
Anticancer drugs - methotrexate and irinotecan
Sartans – olmesartan and valsartan
Rifampicin
Mycophenolic acid
Torsemide
Thiazolidine diones – pioglitazone and rosiglitazone
Glinides – nateglinide and repaglinide
Lopinavir
Fexofenadine
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 Investigation
Search 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.
Genetic Counseling
Genetic counseling is the process of providing individuals and families with
information on the nature, inheritance, and implications of genetic disorders to help them
make informed medical and personal decisions. The following section deals with genetic
risk assessment and the use of family history and genetic testing to clarify genetic
status for family members. This section is not meant to address all personal, cultural, or
ethical issues that individuals may face or to substitute for consultation with a genetics
professional. —ED.
Mode of Inheritance
Rotor syndrome, inherited in an autosomal recessive manner, requires biallelic pathogenic variants in both SLCO1B1 and SLCO1B3 that result in complete functional deficiencies of both protein products (OATP1B1 and OATP1B3, respectively) [van de Steeg et al 2012].
Risk to Family Members
Parents of a proband
Sibs of a proband
Offspring of a proband. The offspring of an individual with Rotor syndrome are obligate heterozygotes (carriers) for a pathogenic variant in SLCO1B1 and a pathogenic variant in SLCO1B3.
Other family members. Each sib of the proband’s parents is at increased risk of being a carrier.
Carrier Detection
Carrier testing for at-risk family members is possible through laboratories offering either testing for the gene of interest or custom testing.
Prenatal Testing and Preimplantation Genetic Diagnosis
Once the pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.
Requests for prenatal testing for benign, clinically unimportant conditions such as Rotor syndrome are not expected to be common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.
Resources
GeneReviews staff has selected the following disease-specific and/or umbrella
support organizations and/or registries for the benefit of individuals with this disorder
and their families. GeneReviews is not responsible for the information provided by other
organizations. For information on selection criteria, click here.
No specific resources for Rotor Syndrome have been identified by GeneReviews staff.
Molecular Genetics
Information 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 Databases
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Data are compiled from the following standard references: gene from
HGNC;
chromosome locus from
OMIM;
protein from UniProt.
For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click
here.
Table B.
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|
237450 | HYPERBILIRUBINEMIA, ROTOR TYPE; HBLRR |
|
604843 | SOLUTE CARRIER ORGANIC ANION TRANSPORTER FAMILY, MEMBER 1B1; SLCO1B1 |
|
605495 | SOLUTE CARRIER ORGANIC ANION TRANSPORTER FAMILY, MEMBER 1B3; SLCO1B3 |
Molecular 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.
SLCO1B1
Gene structure.
SLCO1B1 comprises one untranslated and 14 protein-coding exons. The only transcript is 2.8 kb long.
Pathogenic 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.
SLCO1B3
Gene structure.
SLCO1B3 comprises one untranslated and 14 protein-coding exons. The only transcript is 2.8 kb long.
Pathogenic 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.
References
Literature Cited
Chowdhury JR, Wolkoff AW, Chowdhury NR, Arias IM. Hereditary jaundice and disorders of bilirubin metabolism. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. Vol 2. New York, NY: McGraw Hill; 2001:3063-101.
Hrebícek M, Jirásek T, Hartmannová H, Nosková L, Stránecký V, Ivánek R, Kmoch S, Cebecauerová D, Vítek L, Mikulecký M, Subhanová I, Hozák P, Jirsa M. Rotor-type hyperbilirubinaemia has no defect in the canalicular bilirubin export pump.
Liver Int. 2007;27:485–91. [
PubMed: 17403188]
Niemi M, Pasanen MK, Neuvonen PJ. Organic anion transporting polypeptide 1B1: a genetically polymorphic transporter of major importance for hepatic drug uptake.
Pharmacol Rev. 2011;63:157–81. [
PubMed: 21245207]
Shitara Y. Clinical importance of OATP1B1 and OATP1B3 in drug-drug interactions.
Drug Metab Pharmacokinet. 2011;26:220–7. [
PubMed: 21297316]
van de Steeg E, Stránecký V, Hartmannová H, Nosková L, Hřebíček M, Wagenaar E, van Esch A, de Waart DR, Oude Elferink RP, Kenworthy KE, Sticová E, al-Edreesi M, Knisely AS, Kmoch S, Jirsa M, Schinkel AH. Complete OATP1B1 and OATP1B3 deficiency causes human Rotor syndrome by interrupting conjugated bilirubin reuptake into the liver.
J Clin Invest. 2012;122:519–28. [
PMC free article: PMC3266790] [
PubMed: 22232210]
