Rotor Syndrome

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Retrieved

2021-01-18

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Gene_reviews

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Genes

SLCO1B1, SLCO1B3, ABCC2

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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 cholestasis or 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 OATP1B1 and OATP1B3 may have serious consequences for liver uptake – and thus for the 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 digenic 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 relatives and prenatal and preimplantation genetic testing are possible if the pathogenic variants have been identified in an affected family member.

Diagnosis

Suggestive Findings

Rotor syndrome should be suspected in individuals with the following clinical and laboratory features.

Clinical features

Mild jaundice (may be intermittent)
Conjunctival icterus (in some affected individuals)
Otherwise normal physical examination

Laboratory features (see Table 1)

Conjugated hyperbilirubinemia with serum total bilirubin concentration is usually between 2 and 5 mg/dL but can be higher. Conjugated bilirubin usually exceeds 50% of total bilirubin.
Presence of bilirubin in the urine
Absence of hemolysis*
Normal serum ALT, AST, ALP, and γ-GT activity*
Cholescintigraphy
Total urinary porphyrins: elevated coproporphyrin

* 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

Table 1.

Laboratory Findings in Rotor Syndrome

Finding		Rotor Syndrome	Normal
Serum bilirubin	Total	2-5 mg/dL ¹	0.3-1.0 mg/dL ²
Serum bilirubin	Conjugated: total	>50%	<20%
Urine	Bilirubin	Present	Not detected
Urine	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 & 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].

Establishing the Diagnosis

The diagnosis of Rotor syndrome is established in a proband with isolated, predominantly conjugated hyperbilirubinemia without cholestasis or liver injury and typical findings on cholescintigraphy (Table 1). 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 (see Table 2).

Molecular genetic testing approaches can include a combination of concurrent gene testing and multigene panel:

Concurrent gene testing. Sequence analysis of SLCO1B1 and SLCO1B3 detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. Perform sequence analysis first. If biallelic pathogenic variants in SLCO1B1 and SLCO1B3 are not found, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications.
A multigene panel that includes SLCO1B1, SLCO1B3, and other genes of interest (see Differential Diagnosis) can be considered to identify the genetic cause of the condition at the most reasonable cost 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 this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see Table 2).
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

Gene ^1, 2	Proportion of Rotor Syndrome Attributed to Pathogenic Variants in Gene	Proportion of Pathogenic Variants ³ Detectable by Test Method
Gene ^1, 2		Sequence analysis ⁴	Gene-targeted deletion/duplication analysis ⁵
SLCO1B1	100% ⁶	~75% ^7, 8	~25% ⁷
SLCO1B3	100% ⁶	~50% ^7, 8	~50% ⁷

1.: Genes are listed in alphabetic order.
2.: See Table A. Genes and Databases for chromosome locus and protein.
3.: See Molecular Genetics for information on allelic variants detected in this gene.
4.: Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or 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.: Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
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 [van de Steeg et al 2012].
7.: A biallelic whole-gene deletion spanning both SLCO1B1 and SLCO1B3 was present in four families. A biallelic nonsense variant in SLCO1B1 and a biallelic deletion of exon 12 in SLCO1B3 were present in three families. A nonsense variant in SLCO1B1 and a biallelic splice site variant in SLCO1B3 were present in one family [van de Steeg et al 2012].
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 SLCO1B1 resulting in aberrant splicing. The L1 retrotransposon insertion is not detected by routine sequence analysis but can be detected by allele-specific PCR designed to amplify and sequence the insertion breakpoint.

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.

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 lower than expected.

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, which is benign and common;
Crigler-Najjar syndrome type II, which is benign and rare; 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 hereditary jaundice are included in the differential diagnosis.

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 3. In addition to jaundice, abdominal pain and hepatomegaly may be present in some persons with DJS – although, like Rotor syndrome, DJS is typically benign. DJS is caused by pathogenic variants in ABCC2.

Table 3.

Comparison of Findings in Dubin-Johnson Syndrome and Rotor Syndrome

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
Serum bilirubin	Conjugated: total	>50%	>50%	<20%
Urine	Bilirubin	Present; urine may be dark	Present; urine may be dark	Not detected
Urine	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 ^14, 15	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.: May be higher
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 (BSP), indocyanin 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.
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 histopathologic findings are 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 typically 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 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.

Gilbert syndrome (OMIM 143500) is an autosomal recessive disorder of bilirubin metabolism caused by pathogenic variants in UGT1A1 that decrease the rate of bilirubin conjugation catalyzed by UGT1A1. The variants include the promoter TATA repeat variation A(TA)₇TAA (normal A(TA)₆TAA), which is often combined with the promoter SNP c.-3279T>G), or missense variants in the coding region of UGT1A1, which are frequent in the Japanese population but rare in Europeans.

Hyperbilirubinemia <6 mg/dL 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.

Crigler-Najjar syndrome type II (or Arias syndrome) (OMIM 606785) is an autosomal recessive benign disorder similar to Gilbert syndrome, caused by pathogenic variants in the coding region of UGT1A1 and characterized by predominantly unconjugated hyperbilirubinemia ranging from 6 to 20 mg/dL.

Gilbert syndrome and Crigler-Najjar syndrome type II represent two phenotypes caused by pathogenic variants with quantitatively different consequences on the UGT1A1 enzyme activity. Since plasma bilirubin level is not stable, the two phenotypes may overlap in the same individuals. However, unconjugated hyperbilirubinemia associated with homozygous A(TA)₇TAA genotype but no pathogenic variants in the coding regions of UGT1A1 should always be diagnosed as Gilbert syndrome.

See Hyperbilirubinemia: OMIM Phenotypic Series to view genes associated with this phenotype in OMIM.

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.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Rotor syndrome, the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended:

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].

Statins – simvastatin, atorvastatin, pravastatin, pitavastatin, rosuvastatin
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
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.