Rotor Syndrome

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.

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

Establishing the Diagnosis

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

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.

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

Evaluation of Relatives at Risk

See 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 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.

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).
• If a molecular diagnosis has been established in the proband, molecular genetic testing of the parents of the proband can confirm their genetic status and allow reliable recurrence risk assessment.
• 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.

Related Genetic Counseling Issues

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.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

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.

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

Table 5.

Gene-Specific Laboratory Considerations

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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