Rotor Syndrome
Synonym: Rotor-Type Hyperbilirubinemia
Milan Jirsa, MD, PhD, AS Knisely, MD, Alfred Schinkel, PhD, and Stanislav Kmoch, PhD.
Author Information and AffiliationsInitial Posting: December 13, 2012; Last Update: February 27, 2025.
Estimated reading time: 16 minutes
Summary
Clinical characteristics.
Rotor syndrome is characterized by mild 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.
Diagnosis/testing.
The diagnosis of Rotor syndrome is established in a proband with isolated, predominantly conjugated hyperbilirubinemia without cholestatic liver injury and typical findings on cholescintigraphy. Identification of biallelic pathogenic variants in SLCO1B1 and SLCO1B3 on molecular genetic testing can confirm the diagnosis when cholescintigraphy is either not available or not recommended due to risks associated with the procedure.
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 SLCO1B1 and SLCO1B3 may have serious consequences for liver uptake – and thus for the toxicity of numerous commonly used drugs and/or their metabolites.
Genetic counseling.
Rotor syndrome is inherited in an autosomal recessive digenic manner that clinically resembles monogenic autosomal recessive inheritance. (Although Rotor syndrome is a digenic disorder, pathogenic variants in SLCO1B1 and SLCO1B3 are unlikely to segregate independently.) If both parents are known to be heterozygous for SLCO1B1 and SLCO1B3 pathogenic variants in cis, each sib of an affected individual has at conception a 25% chance of inheriting biallelic pathogenic variants in both SLCO1B1 and SLCO1B3 and being affected; a 50% chance of being an asymptomatic carrier; and a 25% chance of being unaffected and not a carrier. Carriers (i.e., individuals with one, two, or three pathogenic variants) are asymptomatic and are not at risk of developing Rotor syndrome. Once the Rotor syndrome-causing pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.
Diagnosis
Suggestive Findings
Rotor syndrome should be suspected in individuals with the following clinical, laboratory, and cholescintigraphy findings and family history.
Clinical findings
Mild jaundice (may be intermittent)
Conjunctival icterus (in some affected individuals)
Otherwise normal physical examination
Laboratory findings (See Table 1.)
Conjugated hyperbilirubinemia with serum total bilirubin concentration usually between 2 and 5 mg/dL but possibly higher. Conjugated bilirubin usually exceeds 50% of total bilirubin.
Presence of bilirubin in the urine
Absence of hemolysis*
Normal serum alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), and gamma-glutamyl transferase (GGT) activity*
Total urinary porphyrins: elevated coproporphyrin
* Tests for hemolysis and measurements of ALT, AST, ALP, and GGT activity are needed to evaluate for hemolytic anemia and hepatobiliary diseases that are considered in the differential diagnosis of Rotor syndrome.
Cholescintigraphy findings. 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, the cardiac blood pool is persistently visualized, with prominent excretion by the kidneys.
Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.
Table 1.
Laboratory Findings in Rotor Syndrome
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Laboratory Finding | Rotor Syndrome | Normal |
---|
Blood
|
Total bilirubin
| 2-5 mg/dL 1 | 0.3-1.0 mg/dL 2 |
Conjugated:total bilirubin ratio
| >50% | <20% |
Liver enzymes
| Normal | Normal |
Hemolysis
| None | None |
Urine
|
Bilirubin
| Present | Not detected |
Coproporphyrins
| ↑ 2.5-5x normal 3 | |
- 1.
- 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. It is not specific to Rotor syndrome.
Establishing the Diagnosis
Clinical Diagnosis
The clinical diagnosis of Rotor syndrome can be established in a proband with isolated, predominantly conjugated hyperbilirubinemia without cholestasis or liver injury and typical findings on cholescintigraphy.
Molecular Diagnosis
Identification of biallelic pathogenic (or likely pathogenic) variants in SLCO1B1
and
SLCO1B3 on molecular genetic testing can confirm the diagnosis when cholescintigraphy is either not available or not recommended due to risks associated with the procedure (see Table 2).
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of biallelic variants of uncertain significance (or of one known pathogenic variant and one variant of uncertain significance) does not establish or rule out the diagnosis.
Molecular genetic testing approaches can include a combination of concurrent gene testing and multigene panel testing.
Concurrent gene testing. Sequence analysis of
SLCO1B1 and
SLCO1B3 detects
missense,
nonsense, and
splice site variants and small intragenic deletions/insertions. Note: Depending on the sequencing method used, single-
exon, multiexon, or whole-gene deletions/duplications may not be detected. If only one or no variant is detected by the sequencing method used, the next step is to perform gene-targeted
deletion/duplication analysis to detect exon and whole-gene deletions or duplications.
A multigene panel that includes
SLCO1B1,
SLCO1B3, and other genes of interest (see
Differential Diagnosis) may be considered to identify the genetic cause of the condition while limiting identification of variants of
uncertain significance and pathogenic variants in genes that do not explain the underlying
phenotype. Note: (1) The genes included in the panel and the diagnostic
sensitivity of the testing used for each
gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this
GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused
exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include
sequence analysis,
deletion/duplication analysis, and/or other non-sequencing-based tests.
For an introduction to multigene panels click
here. More detailed information for clinicians ordering genetic tests can be found
here.
Table 2.
Molecular Genetic Testing Used in Rotor Syndrome
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Gene 1, 2 | Proportion of Rotor Syndrome Attributed to Pathogenic Variants in Gene | Proportion of Pathogenic Variants 3 Identified by Method |
---|
Sequence analysis 4 | Gene-targeted deletion/duplication analysis 5 |
---|
SLCO1B1
| 100% 6 | 80% 7, 8 | 20% 7 |
SLCO1B3
| 60% 7, 8 | 40% 7 |
- 1.
Genes are listed in alphabetic order.
- 2.
- 3.
- 4.
- 5.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
- 6.
The Rotor syndrome locus comprises both SLCO1B1 and SLCO1B3, which lie very close together on the same chromosome. All individuals with Rotor syndrome who have undergone molecular testing have had biallelic inactivating pathogenic variants in both SLCO1B1 and SLCO1B3.
- 7.
A splice site variant, a 7.2-kb deletion removing exon 13, a 6.1-kb LINE-1 (L1) insertion in intron 5, and a complex rearrangement in which insertion of L1 in intron 3 is directly followed by a 1185-bp inversion encompassing exon 4, were found in SLCO1B3. A 405-kb deletion including exons 4-16 of SLCO1B3 and the entire deletion of SLCO1B1 has also been reported. Data are derived from the subscription-based professional view of Human Gene Mutation Database [Stenson et al 2020].
- 8.
Of the seven individuals reported by Kagawa et al [2015] with biallelic SLC01B1 and SLC01B3 pathogenic variants, six individuals of Japanese ancestry were homozygous for an insertion of a ~6.1-kb L1 retrotransposon in intron 5 of SLCO1B3 resulting in aberrant splicing. One individual with a homozygous null variant in SLCO1B1 and a complex rearrangement in SLCO1B3 in which insertion of L1 in intron 3 is directly followed by a 1185-bp inversion encompassing exon 4 was reported by Zhou et al [2020].
Other Testing
Liver biopsy. Liver histology is normal in persons with Rotor syndrome; therefore, suspicion of hereditary jaundice is not an indication for liver biopsy. Immunohistologic staining does not detect hepatic proteins SLCO1B1 and SLCO1B3 at the sinusoidal membrane of hepatocytes. Note: Expression of MRP2, frequently absent in Dubin-Johnson syndrome, is normal [Hrebícek et al 2007], and dark melanin-like pigment in hepatocytes typical of Dubin-Johnson syndrome is not present (see Differential Diagnosis).
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 variant that results in reduced activity in one allele of either SLCO1B1 or SLCO1B3 with deleterious variants affecting the remaining three alleles has not been documented.
Prevalence
The prevalence of Rotor syndrome is unknown but is very low (<1:1,000,000).
A high carrier frequency of an insertion of a ~6.1-kb L1 retrotransposon in intron 5 of SLCO1B3 resulting in aberrant splicing was discovered in East Asian populations (10.1%), especially in Southern Han Chinese (18.5%) [Kagawa et al 2015, Kim et al 2022], but this pathogenic variant was almost absent in other studied populations.
Differential Diagnosis
Inherited disorders of bilirubin clearance can present with either conjugated or unconjugated hyperbilirubinemia. Dubin-Johnson syndrome, a benign conjugated hyperbilirubinemia similar to Rotor syndrome, is caused by decreased secretion of conjugated bilirubin into bile. Defects in bilirubin conjugation resulting in increased levels of unconjugated bilirubin are represented by Gilbert syndrome, Crigler-Najjar syndrome type II, and Crigler-Najjar syndrome type I (a rare, severe, life-threatening disease associated with kernicterus typically manifesting within the first days after birth). Since Rotor syndrome is usually diagnosed after the neonatal period, only benign forms of genetic jaundice are included in the differential diagnosis (see Table 3).
Table 4.
Comparison of Findings in Dubin-Johnson Syndrome and Rotor Syndrome
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Finding | Rotor Syndrome | Dubin-Johnson Syndrome | Normal |
---|
Blood
|
Total bilirubin
| 2-5 mg/dL 1 | 2-5 mg/dL 1 | 0.3-1.0 mg/dL 2 |
Conjugated:total bilirubin ratio
| >50% | >50% | <20% |
Liver enzymes 3
| Normal | Normal | Normal |
Hemolysis 4
| None | None | None |
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 5 | <200 μg in 24 hrs 6 |
Disappearance of plasma anionic compounds 7
| Severely delayed | Delayed | Rapid |
Cholescintigraphy
| Scarcely visualized on cholescintigraphy, w/slow liver uptake, persistent visualization of cardiac blood pool, & prominent kidney excretion | Visualization of liver is normal or somewhat delayed but filling of gallbladder is absent or delayed. | Normal |
- 1.
- 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.
Serum alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), and gamma-glutamyl transferase (GGT) activity
- 4.
Red blood count and reticulocyte count
- 5.
Total urinary porphyrin output is normal; however, predominance of coproporphyrin isomer I among urinary porphyrin species is observed on chromatography.
- 6.
Total urinary porphyrin output
- 7.
Includes bromosulfophthalein (BSP), indocyanine green, and cholescintigraphy radiotracers (99mTc-HIDA/99mTc-N [2,6-dimethylphenyl-carbamoylmethyl] iminodiacetic acid, 99mTc-DISIDA/disofenin, 99mTc-BrIDA/mebrofenin). Note: In Dubin-Johnson syndrome, BSP conjugates reappear in the blood after administration of unconjugated BSP; this is not the case in Rotor syndrome.
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 alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), and gamma-glutamyl transferase (GGT) activity. The same holds true for any abnormal findings in the gallbladder and the biliary tree obtained by imaging and/or endoscopy techniques. (See also Pediatric Genetic Cholestatic Liver Disease Overview.)
Hemolytic jaundice is characterized by predominantly unconjugated hyperbilirubinemia and signs of increased hemolysis.
Management
No clinical practice guidelines for Rotor syndrome have been published as no treatment or surveillance is recommended.
Evaluations Following Initial Diagnosis
In most instances an individual diagnosed with Rotor syndrome is the child of a consanguineous couple. In some centers, identification of consanguinity may be an indication for consultation with a clinical geneticist, certified genetic counselor, certified genetic nurse, or genetics advanced practice provider (nurse practitioner or physician assistant).
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 SLCO1B1 and SLCO1B3 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 SLCO1B1 and whose pharmacokinetics are known to be influenced by genetic variability in SLCO1B1 or inhibition of SLCO1B1/3 has been published [Niemi et al 2011, Garrison et al 2020, Anabtawi et al 2022]. Some of these drugs are also taken up by SLCO1B3 [Shitara 2011].
Statins – simvastatin, atorvastatin, pravastatin, pitavastatin, rosuvastatin
Ezetimibe
Anticancer drugs – methotrexate and irinotecan, cabazitaxel, some tyrosine kinase inhibitors (e.g., sunitinib)
Sartans – olmesartan and valsartan
Rifampicin
Mycophenolic acid
Torsemide
Thiazolidine diones – pioglitazone and rosiglitazone
Glinides – nateglinide and repaglinide
Lopinavir
Fexofenadine
Cyclosporin A
Pregnancy Management
No special pregnancy management issues from the perspective of either an affected mother or 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 in the US and EU Clinical Trials Register in Europe for 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, mode(s) of 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; it is not meant to address all personal, cultural, or
ethical issues that may arise or to substitute for consultation with a genetics
professional. —ED.
Mode of Inheritance
Rotor syndrome is inherited in an autosomal recessive digenic manner. It is caused by biallelic pathogenic variants in both SLCO1B1 and SLCO1B3 that result in complete functional deficiencies of both protein products (SLCO1B1 and SLCO1B3, respectively) [van de Steeg et al 2012].
Note: Although Rotor syndrome is a digenic disorder, pathogenic variants in SLCO1B1 and SLCO1B3 are unlikely to segregate independently and, consequently, the pattern of inheritance of Rotor syndrome is similar to that of monogenic autosomal recessive disorders.
Risk to Family Members
Parents of a proband
The parents of an affected child are presumed to be
heterozygous for pathogenic variants in both
SLCO1B1 and
SLCO1B3 (i.e.,
SLCO1B1 and
SLCO1B3 pathogenic variants in
cis)
.Individuals with
heterozygous SLCO1B1 and
SLCO1B3 pathogenic variants in
cis (carriers) are asymptomatic and are not at risk of developing Rotor syndrome. Hyperbilirubinemia develops only in persons with
biallelic inactivating pathogenic variants in both
SLCO1B1 and
SLCO1B3 [
van de Steeg et al 2012]; the presence of at least one
wild type (functional)
allele of either
SLCO1B1 or
SLCO1B3 prevents Rotor-type hyperbilirubinemia.
Sibs of a proband
If both parents are known to be
heterozygous for
SLCO1B1 and
SLCO1B3 pathogenic variants in
cis, each sib of an affected individual has at conception a 25% chance of inheriting
biallelic pathogenic variants in both
SLCO1B1 and
SLCO1B3 and being affected, a 50% chance of being an asymptomatic
carrier, and a 25% chance of being unaffected and not a carrier.
Carriers (i.e., individuals with one, two, or three pathogenic variants) are asymptomatic and are not at risk of developing Rotor syndrome.
Offspring of a proband. Unless an affected individual's reproductive partner also has Rotor syndrome or is a carrier, offspring will be obligate heterozygotes (carriers) for pathogenic variants in SLCO1B1 and SLCO1B3.
Other family members. Each sib of the proband's parents is at 50% risk of being a carrier for SLCO1B1 and SLCO1B3 pathogenic variants.
Carrier Detection
Carrier testing for at-risk relatives requires prior identification of the SLCO1B1 and SLCO1B3 pathogenic variants in the family.
Prenatal Testing and Preimplantation Genetic Testing
Once the Rotor syndrome-causing pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing 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 and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
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.
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
View in own window
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.
View in own window
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 Pathogenesis
In individuals with Rotor syndrome, liver histologic findings are normal; however, expression of SLCO1B1 (solute carrier organic anion transporter family member 1B1, encoded by SLCO1B1; also known as OATP1B1) and SLCO1B3 (solute carrier organic anion transporter family member 1B3, encoded by SLCO1B3; also known as 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 SLCO1B1 and SLCO1B3 also explains the poor uptake by the liver of unconjugated bilirubin and anionic dyes such as bromosulfophthalein, indocyanine green, and cholescintigraphy radiotracers (99mTc-HIDA and related compounds). It also underlies earlier observations that in individuals with Rotor syndrome conjugated bromosulfophthalein does not appear in the blood after intravenous administration of its unconjugated precursor. Impaired uptake and biliary secretion of indocyanine green has been attributed to isolated SLCO1B3 deficiency [Kagawa et al 2017]. Whether simultaneous presence of SLCO1B1 and SLCO1B3 deficiency is essential for impaired uptake of bromosulfophthalein and cholephilic radiotracers remains to be established.
Reduced hepatic (re)uptake of coproporphyrin isomers probably underlies the increased urinary excretion of coproporphyrins.
Mechanism of disease causation. Loss of function
Chapter Notes
Author Notes
Milan Jirsa (zc.meki@ijim) is actively involved in clinical research regarding individuals with Rotor syndrome. Dr Jirsa would be happy to communicate with persons who have any questions regarding diagnosis of Rotor syndrome or other considerations.
Dr Jirsa is also interested in hearing from clinicians treating families affected by Rotor syndrome in whom no causative variant has been identified through molecular genetic testing of the genes known to be involved in this group of disorders.
Contact Dr Jirsa to inquire about review of SLCO1B1 or SCLO1B3 variants of uncertain significance.
Acknowledgments
Milan Jirsa has been supported by DRO IKEM IN 00023001.
Revision History
27 February 2025 (sw) Comprehensive update posted live
11 July 2019 (sw) Comprehensive update posted live
13 December 2012 (bp) Review posted live
6 September 2012 (mj) Original submission
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