Clinical characteristics.

Sitosterolemia is characterized by:

• Hypercholesterolemia (especially in children) which (1) shows an unexpected significant lowering of plasma cholesterol level in response to low-fat diet modification or to bile acid sequestrant therapy; or (2) does not respond to statin therapy;
• Tendon xanthomas or tuberous (i.e., planar) xanthomas that can occur in childhood and in unusual locations (heels, knees, elbows, and buttocks);
• Premature atherosclerosis, which can lead to angina, aortic valve involvement, myocardial infarction, and sudden death;
• Hemolytic anemia, abnormally shaped erythrocytes (stomatocytes), and large platelets (macrothrombocytopenia).

On occasion, the abnormal hematologic findings may be the initial presentation or the only clinical feature of this disorder. Arthritis, arthralgias, and splenomegaly may sometimes be seen and one study has concluded that "idiopathic" liver disease could be undiagnosed sitosterolemia. The clinical spectrum of sitosterolemia is probably not fully appreciated due to underdiagnosis and the fact that the phenotype in infants is likely to be highly dependent on diet.

Diagnosis/testing.

In an individual with sitosterolemia, increased plasma concentrations of plant sterols (especially sitosterol, campesterol, and stigmasterol) are observed – if the diet includes plant-derived food, which contain plant sterols – once the plant sterols have accumulated in the body. The diagnosis of sitosterolemia is established in a proband with greatly increased plant sterol concentrations in plasma and/or by identification of biallelic pathogenic (or likely pathogenic) variants in ABCG5 and/or ABCG8.

Management.

Treatment of manifestations: Treatment should begin at the time of diagnosis, though there is little experience treating children younger than age two years. Treatment can decrease plasma concentrations of cholesterol and sitosterol by 10% to 50%. Often existing xanthomas regress. Treatment recommendations include a diet low in shellfish sterols and plant sterols (vegetable oils, margarine, nuts, seeds, avocados, and chocolate) and use of the sterol absorption inhibitor, ezetimibe. In those with an incomplete response to ezetimibe, use of a bile acid sequestrant such as cholestryramine may be considered. Partial ileal bypass surgery may be considered as a last resort for those with poor response to maximal therapies. If arthritis, arthralgias, anemia, thrombocytopenia, and/or splenomegaly require treatment, the first step is management of the sitosterolemia, followed by routine symptomatic management.

Surveillance: Begin monitoring at the time of diagnosis on an annual basis: plasma concentrations of plant sterols (primarily beta-sitosterol and campesterol) and cholesterol; the size, number, and distribution of xanthomas; and CBC and platelet count, and liver transaminases (for elevation). In persons with long-standing untreated sitosterolemia, noninvasive imaging is used to exclude coronary and carotid plaque as well as valvular atherosclerotic manifestations.

Agents/circumstances to avoid: Margarines and other products containing stanols (e.g., campestanol and sitostanol) that are recommended for use by persons with hypercholesterolemia are contraindicated as they can exacerbate plant stanol accumulation.

Evaluation of relatives at risk: Early diagnosis of at-risk relatives either through measurement of plasma concentrations of plant sterols or through molecular genetic testing (if the family-specific pathogenic variants are known) allows early institution of treatment and surveillance to optimize outcome.

Pregnancy management: There are no adequate and well-controlled studies of ezetimibe in pregnant women; ezetimibe can be used during pregnancy only if the potential benefits justifiy the risk to the fetus. Since no studies have been published on the fetal effects of ezetimibe, it should be used with caution during pregnancy.

Genetic counseling.

Sitosterolemia is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Heterozygotes (carriers) are asymptomatic but may occasionally have a mildly elevated concentration of sitosterol. Once the sitosterolemia-causing pathogenic variants have been identified in an affected family member, carrier testing for at-risk family members, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.

Suggestive Findings

Sitosterolemia should be suspected in individuals with the following:

• Hypercholesterolemia (especially in children) that shows unexpected significant response (i.e., lowering of plasma cholesterol level) to low-fat diet modification (e.g., low saturated fat/low cholesterol/low plant-derived foods) or to bile acid sequestrant (e.g. cholestyramine) therapy [Cobb et al 1996, Park et al 2014]
• Hypercholesterolemia that does not respond to statin therapy [Nguyen et al 1990, Cobb et al 1996]
• Tendon xanthomas or tuberous xanthomas, which may occur in childhood and in unusual locations (heels, knees, elbows, and buttocks) [Niu et al 2010]
• Premature atherosclerosis, which may lead to angina, myocardial infarction, and sudden death [Kidambi & Patel 2008]
• Hemolytic anemia usually associated with abnormally shaped erythrocytes (stomatocytes) and/or thrombocytopenia usually associated with large platelets (macrothrombocytopenia)
  Note: The hematologic abnormalities can be the initial presentation [Rees et al 2005, Su et al 2006] or the only clinical feature of the disorder [Wang et al 2011].

Note: The complete clinical spectrum of sitosterolemia is probably not fully appreciated due to underdiagnosis. Furthermore, the phenotype in infants is likely to be highly dependent on diet.

Establishing the Diagnosis

The diagnosis of sitosterolemia is established in a proband with greatly increased plant sterol concentrations in plasma and/or by identification of biallelic pathogenic (or likely pathogenic) variants in one or both of the genes listed in Table 1.

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) in one or both of the genes listed in Table 1 does not establish or rule out the diagnosis.

Measurement of plasma plant sterol concentrations. Individuals with sitosterolemia have greatly increased plant sterol concentrations (especially sitosterol, campesterol, and stigmasterol) in plasma. Shellfish sterols can also be elevated.

• Typical plant sterol concentrations in healthy individuals are 100 times lower than cholesterol (0.21 ± 0.7 mg/dL); thus, their contribution to the total sterol concentration is negligible. These plant sterols and shellfish sterols are not detected by standard laboratory methods of cholesterol measurement and require specialized analysis typically utilizing gas chromatography (GC), gas chromatography / mass spectrometry (GC/MS), high-pressure liquid chromatography (HPLC) or separation with tandem mass spectrometry (LC-MS/MS).
• In untreated individuals with sitosterolemia the sitosterol concentration can be 30- to 100-fold increased (i.e., as high as 10 to 65 mg/dL) [Kidambi & Patel 2008]. Plasma concentrations of sitosterol above 1 mg/dL are considered to be diagnostic of sitosterolemia (except in infants, in whom further testing may be necessary; see following Note).
  Note: (1) In individuals with sitosterolemia the plant sterol transporters sterolin-1 (encoded by ABCG5) and sterolin-2 (encoded by ABCG8) are abnormal at birth; however, the increase in the plasma concentration of sitosterol and other plant sterols does not occur until plant-derived foods (which contain plant sterols) are consumed and the plant sterols accumulate in the body. Thus, even using GC, GC/MS, HPLC, or LC-MS/MS to measure plasma sitosterol concentrations, the diagnosis of sitosterolemia cannot be excluded until the child is consuming foods that contain plant oils. Formula-fed infants with sitosterolemia may have high plasma concentrations of cholesterol and plant sterols. (2) Total parenteral nutrition with intralipid often contains plant sterols; caution is advised in interpreting diagnostic testing for sitosterolemia in this situation. (3) Breast-fed infants with sitosterolemia likely will not have increased concentrations of plant sterols until after weaning [Rios et al 2010]. Of note, one breastfed infant age three months with sitosterolemia had increased plasma concentrations of sitosterol [Niu et al 2010].

False positive results have been observed:

• Normal infants ingesting commercial infant formula (which contains plant sterols) may have a transient increase in plasma plant sterols, probably due to immature transporters [Mellies et al 1976, Steiner 2011].
• Patients with cholestasis or liver disease receiving parenteral nutrition (which often contains plant sterols in intralipids) may be unable to effectively clear the plant sterols [Bindl et al 2000, Llop et al 2008, Kurvinen et al 2011]. Infants without obvious cholestasis or liver disease receiving parenteral nutrition who do not have sitosterolemia may also exhibit elevation of plasma plant sterols.
• Heterozygotes (carriers of one ABCG5 or ABCG8 pathogenic variant) may occasionally have mildly elevated concentration of sitosterol [Lee et al 2001], which can be exacerbated with plant sterols [Myrie et al 2012]. (Note, however, that plasma concentrations of sitosterol are usually normal in carriers [Kwiterovich et al 2003]).

False negative results can be observed in:

• Individuals using ezetimibe or ezetimibe combinations, or bile acid-binding resin;
  AND/OR
• Individuals on a diet low in plant-derived foods.

Note: (1) In general plasma cholesterol concentration is not diagnostic because it can be normal in individuals with sitosterolemia, and elevations of plasma cholesterol concentration can be seen in numerous common disorders. (2) In sitosterolemia, plasma concentrations of cholesterol in children can be high, even in the range seen in homozygous familial hypercholesterolemia [Togo et al 2009, Niu et al 2010, Rios et al 2010, Renner et al 2016].

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of sitosterolemia has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

To date, approximately 110 individuals with biallelic pathogenic variants in ABCG5 and/or ABCG8 have been reported [Berge et al 2000, Hubacek et al 2001, Lu et al 2001, Heimerl et al 2002, Sehayek et al 2004, Wang et al 2004, Wilund et al 2004, Rees et al 2005, Solcà et al 2005, Su et al 2006, Kratz et al 2007, Mannucci et al 2007, Togo et al 2009, Niu et al 2010, Rios et al 2010, Tsubakio-Yamamoto et al 2010, Keller et al 2011, Wang et al 2011, Chong et al 2012, Horenstein et al 2013, Colima Fausto et al 2016, Rodriguez et al 2016, Tada et al 2016, Bardawil et al 2017, Bastida et al 2017, Buonuomo et al 2017, Jamwal et al 2017, Ono et al 2017, Yagasaki et al 2017, Brinton et al 2018, Fang et al 2018, Kawamura et al 2018, Martin et al 2018, Tada et al 2018, Huang et al 2019, Su et al 2019, Tada et al 2019, Veit et al 2019, Wang et al 2019, Sun et al 2020]. The following description of the phenotypic features associated with this condition is based on these reports.

Presentation. The clinical presentation of sitosterolemia varies from xanthomas and atherosclerosis and its complications to a milder phenotype with few to no specific symptoms and signs [Kidambi & Patel 2008].

Hypercholesterolemia. Individuals with sitosterolemia show an unexpected significant lowering of plasma cholesterol level in response to low-fat or low plant-derived food diet modification or to bile acid sequestrant therapy, and do not respond to statin therapy.

There is evidence of an age-related change in sterol homeostasis in sitosterolemia, where plasma concentrations of cholesterol in children with sitosterolemia can be in the hypercholesterolemia range and decrease to normal cholesterol levels by adulthood [Mymin et al 2018].

Tendon or tuberous xanthomas. Although the tuberous xanthomas are more typically seen in adults, they may appear at any age, even in children. Children may have xanthomas in unusual locations such as the buttocks, heels, elbows, and knees. Xanthomas have been reported in children as young as ages one to two years [Shulman et al 1976, Hubacek et al 2001, Niu et al 2010], four years [Togo et al 2009], and six years [Salen et al 2006, Mannucci et al 2007]. A child age ten years with tendon xanthomas was reported [Solcà et al 2005].

Premature atherosclerosis. Ten individuals with sitosterolemia with early-onset (age 5-33 years) atherosclerosis with or without sudden death have been reported [Miettinen 1980, Kwiterovich et al 1981, Salen et al 1985, Watts & Mitchell 1992, Kolovou et al 1996, Heimerl et al 2002, Katayama et al 2003, Mymin et al 2003, Salen et al 2006, Tsubakio-Yamamoto et al 2010].

• Assessment for premature atherosclerosis should include noninvasive imaging to exclude coronary and carotid plaque as well as atherosclerotic manifestations (e.g., heart murmurs and vascular bruits).
• Because of the limited number of reports, the incidence of coronary artery disease is not known.

Hematologic abnormality. Hemolytic anemia and/or thrombocytopenia can be the initial presentation [Rees et al 2005, Su et al 2006] or the only clinical feature of the disorder [Wang et al 2011, Zheng et al 2019]. The hemolytic anemia may be associated with low hemoglobin levels of 76 to 109 g/L and the thrombocytopenia has been reported with platelet counts as low as 12 to 82 x 10⁹/L [Wang et al 2014, Zheng et al 2019].

Other findings

• On occasion arthritis, arthralgias, and splenomegaly are also seen.
• Miettinen et al [2006] described an individual with chronic non-A non-B hepatitis and cirrhosis in whom the diagnosis of sitosterolemia was serendipitously made by plasma analysis of sitosterol, and further confirmed by the finding of the biallelic ABCG8 pathogenic variants. Following liver transplantation, the sitosterolemia unexpectedly resolved and plant sterol levels fell to the same levels seen in unaffected individuals. Although it is unknown if the liver problem was initially due to the sitosterolemia, the findings suggest that "idiopathic" liver disease could indeed be undiagnosed sitosterolemia. The authors concluded that an unaffected liver can overcome the intestinal transport defect in clearing the plant sterols from the circulation.

Intrafamilial variability has been reported in two consanguineous families:

• In one family, phenotypic variablilty was seen in three affected sibs and one affected first cousin with the same genotype [Wang et al 2004]. One child had abdominal pain, anemia, xanthomas, and early cardiac death; the others had high plasma concentrations of cholesterol and plant sterols but no other symptoms.
• In another family the mother and brother of the proband were homozygous for the same nucleotide change in ABCG5. All had increased concentrations of plasma sitosterol; however, only the proband (age 6 years) had xanthomas. The mother and brother, who had no evidence of xanthomas, had much lower cholesterol concentrations [Mannucci et al 2007].

Genotype-Phenotype Correlations

No genotype-phenotype correlations for ABCG5 and ABCG8 have been identified.

Nomenclature

The disorder was named β-sitosterolemia by the investigators who first described it [Bhattacharyya & Connor 1974].

Prevalence

To date, about 110 individuals with molecularly confirmed sitosterolemia have been reported worldwide [Tada et al 2018].

Because the usual clinical test for plasma concentration of cholesterol does not measure plant sterols, sitosterolemia is likely to be underdiagnosed. In a population-based study, the data suggest a much higher prevalence than that indicated by the small number of known cases [Wilund et al 2004]; these researchers identified one individual with sitosterolemia out of 2542 persons in whom plasma concentration of plant sterols was analyzed, data that support a prevalence of 1/384 to 1/48,076 (95% confidence interval).

Sitosterolemia has been described in persons of Hutterite, Amish, Japanese, and Chinese ancestry as well as in other populations [Lu et al 2001]. Populations that show a high prevalence include:

• The Old Order Amish. Carrier frequency up to 4%
• North American Hutterites. Carrier frequency 8% [Chong et al 2012]
• The inhabitants of Kosrae (Micronesia). Adult carrier frequency 13% [Sehayek et al 2004]

A founder effect is evident in certain populations [Lu et al 2001]:

• Northern Europeans / individuals of northern European ancestry more frequently have pathogenic variants in ABCG8.
• Chinese, Japanese, and Indian individuals tend to have pathogenic variants in ABCG5.

Hereditary Disorders in the Differential Diagnosis of Sitosterolemia

Other Disorders in the Differential Diagnosis of Sitosterolemia

The combination of hemolysis and thrombocytopenia can occur in the following conditions (in which large platelets are not observed):

• Liver disease
• Thrombotic thrombocytopenic purpura
• Systemic lupus erythematosus (SLE)

Stomatocytosis can be associated with Rh_null condition.

Evaluations Following Initial Diagnosis

Treatment of Manifestations

Treatment should begin at the time of diagnosis, though there is little experience treating children younger than age two years. Treatment can decrease the plasma concentrations of cholesterol and sitosterol by 10% to 50%. Existing xanthomas often regress.

Arthritis, arthralgias, anemia, thromobocytopenia, and/or splenomegaly require treatment, the first step being management of the sitosterolemia, followed by routine management of the finding (by the appropriate consultants) as needed.

Note: Sitosterolemia does not respond to standard statin treatment.

Surveillance

Agents/Circumstances to Avoid

Margarines and other products containing stanols (e.g., campestanol and sitostanol), which are recommended for use by persons with hypercholesterolemia, are contraindicated in those with sitosterolemia as they can exacerbate plant stanol accumulation [Connor et al 2005].

Note: Foods with high plant sterol content including shellfish, vegetable oils, margarine, nuts, avocados, and chocolate should be taken in moderation due to increased intestinal absorption of plant sterols in those with sitosterolemia [Bhattacharyya & Connor 1974].

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from early institution of treatment and surveillance. Evaluations include the following:

• Molecular genetic testing if the ABCG5 or ABCG8 pathogenic variants have been identified in an affected family member
• Measurement of plasma concentrations of plant sterols if the family-specific pathogenic variants are not known

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Guidelines for the management of women with sitosterolemia during pregnancy have not been established.

There are no adequate and well-controlled studies of ezetimibe in pregnant women; ezetimibe can be used during pregnancy only if the potential benefits justify the risk to the fetus (Ezetimibe drug monograph).

See MotherToBaby for further information on medication use during pregnancy.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

Sitosterolemia is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one ABCG5 or ABCG8 pathogenic variant based on family history).
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an ABCG5 or ABCG8 pathogenic variant and to allow reliable recurrence risk assessment. (De novo variants are known to occur at a low but appreciable rate in autosomal recessive disorders [Jónsson et al 2017].)
• Heterozygotes (carriers) are asymptomatic but may occasionally have a mildly elevated concentration of sitosterol [Lee et al 2001].

Sibs of a proband

• If both parents are known to be heterozygous for an ABCG5 or ABCG8 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of unaffected and not a carrier. A sib who inherits biallelic pathogenic variants may be more or less severely affected than the proband.
• Heterozygotes (carriers) are asymptomatic but may occasionally have a mildly elevated concentration of sitosterol.

Offspring of a proband. Unless an affected individual's reproductive partner also has sitosterolemia or is a carrier (see Prevalence and Population screening), offspring will be obligate heterozygotes (carriers) for a pathogenic variant in ABCG5 or ABCG8.

Other family members. Each sib of the proband’s parents is at a 50% risk of being a carrier of an ABCG5 or ABCG8 pathogenic variant.

Carrier Detection

Molecular genetic carrier testing for at-risk family members requires prior identification of the ABCG5 or ABCG8 pathogenic variants in the family.

Note: Carriers cannot be reliably detected by analyte testing.

Related Genetic Counseling Issues

See Evaluation Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, 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.

Population screening. Individuals of North American Hutterite or Amish ancestry may choose to have carrier testing for the ABCG8 p.Ser107Ter founder variant or the ABCG8 p.Gly574Arg founder variant, respectively.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Once the sitosterolemia-causing pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing is possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most centers would regard use of prenatal and preimplantation genetic testing to be a personal choice, discussion of these issues may be helpful.

Molecular Pathogenesis

Sterolin-1 (encoded by ABCG5) and sterolin-2 (encoded by ABCG8) are two ATP-binding cassette half-transporters that belong to the G family members. They function as heterodimers. The highest expression of sterolin-1 and sterolin-2 is in the intestines and liver, functioning to selectively remove plant sterols and resecrete them back into the intestinal lumen and from the liver into the bile [von Bergmann et al 2005].

Defective sterolin heterodimer transporter function increases cholesterol and sitosterol absorption and decreases sitosterol and cholesterol excretion into the bile.

Mechanism of disease causation. Loss of function

Author Notes

Analyte clinical diagnostic testing for sitosterolemia is available here.

The authors conduct research studies on sitosterolemia as part of the Rare Diseases Clinical Research Network: Sterol & Isoprenoid Research Consortium.

Acknowledgments

The current authors would like to acknowledge Louise S Merkens, PhD, retired from Oregon Health & Science University in Portland, Oregon, as an original author whose contributions to the original content of this GeneReview remain extremely important and valuable.

Author History

Louise S Merkens, PhD; Oregon Health & Science University (2012-2020)
David Mymin, MBBCh, FRCP (2012-present)
Semone B Myrie, PhD (2012-present)
Robert D Steiner, MD (2012-present)

Revision History

• 16 July 2020 (ha) Comprehensive update posted live
• 4 April 2013 (me) Review posted live
• 21 February 2012 (lm) Original submission

Literature Cited

• Bardawil T, Rebeiz A, Chaabouni M, El Halabi J, Kambris Z, Abbas O, Abou Hassan O, Hamie L, Bitar F, Ghani Kibbi A, Nemer G, Kurban M. Mutations in the ABCG8 gene are associated with sitosterolaemia in the homozygous form and xanthelasmas in the heterozygous form. Eur J Dermatol. 2017;27:519-23. [PubMed: 28739549]
• Bastida JM, Benito R, Janusz K, Diez-Campelo M, Hernandez-Sanchez JM, Marcellini S, Giros M, Rivera J, Lozano ML, Hortal A, Hernández-Rivas JM, González-Porras JR. Two novel variants of the ABCG5 gene cause xanthelasmas and macrothrombocytopenia: a brief review of hematologic abnormalities of sitosterolemia. J Thromb Haemost. 2017;15:1859-66. [PubMed: 28696550]
• Berge KE, Tian H, Graf GA, Yu L, Grishin NV, Schultz J, Kwiterovich P, Shan B, Barnes R, Hobbs HH. Accumulation of dietary cholesterol in sitosterolemia caused by mutations in adjacent ABC transporters. Science. 2000;290:1771-5. [PubMed: 11099417]
• Bhattacharyya AK, Connor WE. Beta-sitosterolemia and xanthomatosis. A newly described lipid storage disease in two sisters. J Clin Invest. 1974;53:1033-43. [PMC free article: PMC333088] [PubMed: 4360855]
• Bindl L, Lütjohann D, Buderus S, Lentze MJ, v Bergmann K. High plasma levels of phytosterols in patients on parenteral nutrition: a marker of liver dysfunction. J Pediatr Gastroenterol Nutr. 2000;31:313-6. [PubMed: 10997380]
• Brinton EA, Hopkins PN, Hegele RA, Geller AS, Polisecki EY, Diffenderfer MR, Schaefer EJ. The association between hypercholesterolemia and sitosterolemia, and report of a sitosterolemia kindred. J Clin Lipidol. 2018;12:152-61. [PubMed: 29169939]
• Buonuomo PS, Iughetti L, Pisciotta L, Rabacchi C, Papadia F, Bruzzi P, Tummolo A, Bartuli A, Cortese C, Bertolini S, Calandra S. Timely diagnosis of sitosterolemia by next generation sequencing in two children with severe hypercholesterolemia. Atherosclerosis. 2017;262:71-7. [PubMed: 28521186]
• Chong JX, Ouwenga R, Anderson RL, Waggoner DJ, Ober C. A population-based study of autosomal-recessive disease-causing mutations in a founder population. Am J Hum Genet. 2012;91:608-20. [PMC free article: PMC3484657] [PubMed: 22981120]
• Cobb MM, Salen G, Tint GS, Greenspan J, Nguyen LB. Sitosterolemia: opposing effects of cholestyramine and lovastatin on plasma sterol levels in a homozygous girl and her heterozygous father. Metabolism. 1996;45:673-9. [PubMed: 8637439]
• Colima Fausto AG, Gonzalez Garcia JR, Wong Ley Madero LE, Magana Torres MT. Two novel mutations in the ABCG5 gene, c.144 -1G>A and c.1523 delC, in a Mexican family with sitosterolemia. J Clin Lipidol. 2016;10:204-8. [PubMed: 26892138]
• Connor WE, Lin DS, Pappu AS, Frohlich J, Gerhard G. Dietary sitostanol and campestanol: accumulation in the blood of humans with sitosterolemia and xanthomatosis and in rat tissues. Lipids. 2005;40:919-23. [PubMed: 16331855]
• Fang D, Liang LL, Qiu WJ, Fan YJ, Sun Y, Yan H, Yu YG, Gu XF. [Clinical, molecular genetic analysis, and treatment of 3 children with sitosterolemia]. Zhonghua Er Ke Za Zhi. 2018;56:435-9. [PubMed: 29886606]
• Heimerl S, Langmann T, Moehle C, Mauerer R, Dean M, Beil FU, von Bergmann K, Schmitz G. Mutations in the human ATP-binding cassette transporters ABCG5 and ABCG8 in sitosterolemia. Hum Mutat. 2002;20:151. [PubMed: 12124998]
• Horenstein RB, Mitchell BD, Post WS, Lutjohann D, von Bergmann K, Ryan KA, Terrin M, Shuldiner AR, Steinle NI. The ABCG8 G574R variant, serum plant sterol levels, and cardiovascular disease risk in the Old Order Amish. Arterioscler Thromb Vasc Biol. 2013;33:413-9. [PMC free article: PMC3817740] [PubMed: 23241408]
• Huang D, Zhou Q, Chao YQ, Zou CC. Clinical features and genetic analysis of childhood sitosterolemia: two case reports and literature review. Medicine (Baltimore). 2019;98:e15013. [PMC free article: PMC6485811] [PubMed: 30985648]
• Huang SJ, Amendola LM, Sternen DL. Variation among DNA banking consent forms: points for clinicians to bank on. J Community Genet. 2022;13:389-97. [PMC free article: PMC9314484] [PubMed: 35834113]
• Hubacek JA, Berge KE, Cohen JC, Hobbs HH. Mutations in ATP-cassette binding proteins G5 (ABCG5) and G8 (ABCG8) causing sitosterolemia. Hum Mutat. 2001;18:359-60. [PubMed: 11668628]
• Jamwal M, Aggarwal A, Maitra A, Sharma P, Bansal D, Trehan A, Thapa BR, Malhotra P, Das R. First report of Mediterranean stomatocytosis/macrothrombocytopenia in an Indian family: a diagnostic dilemma. Pathology. 2017;49:811-15. [PubMed: 29102041]
• Jónsson H, Sulem P, Kehr B, Kristmundsdottir S, Zink F, Hjartarson E, Hardarson MT, Hjorleifsson KE, Eggertsson HP, Gudjonsson SA, Ward LD, Arnadottir GA, Helgason EA, Helgason H, Gylfason A, Jonasdottir A, Jonasdottir A, Rafnar T, Frigge M, Stacey SN, Th Magnusson O, Thorsteinsdottir U, Masson G, Kong A, Halldorsson BV, Helgason A, Gudbjartsson DF, Stefansson K. Parental influence on human germline de novo mutations in 1,548 trios from Iceland. Nature. 2017; 549: 519-22. [PubMed: 28959963]
• Katayama T, Satoh T, Yagi T, Hirose N, Kurita Y, Anzai T, Asakura Y, Yoshikawa T, Mitamura H, Ogawa S. A 19-year-old man with myocardial infarction and sitosterolemia. Intern Med. 2003;42:591-4. [PubMed: 12879952]
• Kawamura R, Saiki H, Tada H, Hata A. Acute myocardial infarction in a 25-year-old woman with sitosterolemia. J Clin Lipidol. 2018;12:246-9. [PubMed: 29174072]
• Keller S, Prechtl D, Aslanidis C, Ceglarek U, Thiery J, Schmitz G, Jahreis G. Increased plasma plant sterol concentrations and a heterozygous amino acid exchange in ATP binding cassette transporter ABCG5: a case report. Eur J Med Genet. 2011;54:e458-60. [PubMed: 21664501]
• Kidambi S, Patel SB. Sitosterolaemia: pathophysiology, clinical presentation and laboratory diagnosis. J Clin Pathol. 2008;61:588-94. [PubMed: 18441155]
• Kolovou G, Voudris V, Drogari E, Palatianos G, Cokkinos DV. Coronary bypass grafts in a young girl with sitosterolemia. Eur Heart J. 1996;17:965-6. [PubMed: 8781841]
• Kratz M, Kannenberg F, Gramenz E, Berning B, Trautwein E, Assmann G, Rust S. Similar serum plant sterol responses of human subjects heterozygous for a mutation causing sitosterolemia and controls to diets enriched in plant sterols or stanols. Eur J Clin Nutr. 2007;61:896-905. [PubMed: 17228349]
• Kurvinen A, Nissinen MJ, Gylling H, Miettinen TA, Lampela H, Koivusalo AI, Rintala RJ, Pakarinen MP. Effects of long-term parenteral nutrition on serum lipids, plant sterols, cholesterol metabolism, and liver histology in pediatric intestinal failure. J Pediatr Gastroenterol Nutr. 2011;53:440-6. [PubMed: 21543999]
• Kwiterovich PO Jr, Bachorik PS, Smith HH, McKusick VA, Connor WE, Teng B, Sniderman AD. Hyperapobetalipoproteinaemia in two families with xanthomas and phytosterolaemia. Lancet. 1981;1:466-9. [PubMed: 6110091]
• Kwiterovich PO Jr, Chen SC, Virgil DG, Schweitzer A, Arnold DR, Kratz LE. Response of obligate heterozygotes for phytosterolemia to a low-fat diet and to a plant sterol ester dietary challenge. J Lipid Res. 2003;44:1143-55. [PubMed: 12671028]
• Lee MH, Lu K, Patel SB. Genetic basis of sitosterolemia. Curr Opin Lipidol. 2001;12:141-9. [PMC free article: PMC1350992] [PubMed: 11264985]
• Llop JM, Virgili N, Moreno-Villares JM, García-Peris P, Serrano T, Forga M, Solanich J, Pita AM. Phytosterolemia in parenteral nutrition patients: implications for liver disease development. Nutrition. 2008;24:1145-52. [PubMed: 18656327]
• Lu K, Lee MH, Hazard S, Brooks-Wilson A, Hidaka H, Kojima H, Ose L, Stalenhoef AF, Mietinnen T, Bjorkhem I, Bruckert E, Pandya A, Brewer HB Jr, Salen G, Dean M, Srivastava A, Patel SB. Two genes that map to the STSL locus cause sitosterolemia: genomic structure and spectrum of mutations involving sterolin-1 and sterolin-2, encoded by ABCG5 and ABCG8, respectively. Am J Hum Genet. 2001;69:278-90. [PMC free article: PMC1201544] [PubMed: 11452359]
• Mannucci L, Guardamagna O, Bertucci P, Pisciotta L, Liberatoscioli L, Bertolini S, Irace C, Gnasso A, Federici G, Cortese C. Beta-sitosterolaemia: a new nonsense mutation in the ABCG5 gene. Eur J Clin Invest. 2007;37:997-1000. [PubMed: 17976197]
• Martin JM, Cuesta A, Velasco R, Herrero A, Ramon D, Monteagudo C. Two-year-old girl with tuberous xanthomas. J Clin Pathol. 2018;71:860-2. [PubMed: 30232214]
• Mellies M, Glueck CJ, Sweeney C, Fallat RW, Tsang RC, Ishikawa TT. Plasma and dietary phytosterols in children. Pediatrics. 1976;57:60-7. [PubMed: 946132]
• Miettinen TA, Klett EL, Gylling H, Isoniemi H, Patel SB. Liver transplantation in a patient with sitosterolemia and cirrhosis. Gastroenterology. 2006;130:542-7. [PMC free article: PMC1391914] [PubMed: 16472606]
• Miettinen TA. Phytosterolaemia, xanthomatosis and premature atherosclerotic arterial disease: a case with high plant sterol absorption, impaired sterol elimination and low cholesterol synthesis. Eur J Clin Invest. 1980;10:27-35. [PubMed: 6768564]
• Mymin D, Salen G, Triggs-Raine B, Waggoner DJ, Dembinski T, Hatch GM. The natural history of phytosterolemia: observations on its homeostasis. Atherosclerosis. 2018;269:122-8. [PubMed: 29353227]
• Mymin D, Wang J, Frohlich J, Hegele RA. Image in cardiovascular medicine. Aortic xanthomatosis with coronary ostial occlusion in a child homozygous for a nonsense mutation in ABCG8. Circulation. 2003;107:791. [PubMed: 12578886]
• Myrie SB, Mymin D, Triggs-Raine B, Jones PJ. Serum lipids, plant sterols, and cholesterol kinetic responses to plant sterol supplementation in phytosterolemia heterozygotes and control individuals. Am J Clin Nutr. 2012;95:837-44. [PMC free article: PMC3302361] [PubMed: 22378727]
• Nguyen L, Salen G, Shefer S, Shore V, Tint GS, Ness G. Unexpected failure of bile acid malabsorption to stimulate cholesterol synthesis in sitosterolemia with xanthomatosis. Comparison with lovastatin. Arteriosclerosis. 1990;10:289-97. [PubMed: 2317163]
• Niu DM, Chong KW, Hsu JH, Wu TJ, Yu HC, Huang CH, Lo MY, Kwok CF, Kratz LE, Ho LT. Clinical observations, molecular genetic analysis, and treatment of sitosterolemia in infants and children. J Inherit Metab Dis. 2010;33:437-43. [PubMed: 20521169]
• Ono S, Matsuda J, Saito A, Yamamoto T, Fujimoto W, Shimizu H, Dateki S, Ouchi K. A case of sitosterolemia due to compound heterozygous mutations in ABCG5: clinical features and treatment outcomes obtained with colestimide and ezetimibe. Clin Pediatr Endocrinol. 2017;26:17-23. [PMC free article: PMC5295247] [PubMed: 28203044]
• Park JH, Chung IH, Kim DH, Choi MH, Garg A, Yoo EG. Sitosterolemia presenting with severe hypercholesterolemia and intertriginous xanthomas in a breastfed infant: case report and brief review. J Clin Endocrinol Metab. 2014;99:1512-8. [PubMed: 24423340]
• Rees DC, Iolascon A, Carella M, O'marcaigh AS, Kendra JR, Jowitt SN, Wales JK, Vora A, Makris M, Manning N, Nicolaou A, Fisher J, Mann A, Machin SJ, Clayton PT, Gasparini P, Stewart GW. Stomatocytic haemolysis and macrothrombocytopenia (Mediterranean stomatocytosis/macrothrombocytopenia) is the haematological presentation of phytosterolaemia. Br J Haematol. 2005;130:297-309. [PubMed: 16029460]
• Renner C, Connor WE, Steiner RD. Sitosterolemia presenting as pseudohomozygous familial hypercholesterolemia. Clin Med Res. 2016;14:103-8. [PMC free article: PMC5321287] [PubMed: 27231115]
• Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405-24. [PMC free article: PMC4544753] [PubMed: 25741868]
• Rios J, Stein E, Shendure J, Hobbs HH, Cohen JC. Identification by whole-genome resequencing of gene defect responsible for severe hypercholesterolemia. Hum Mol Genet. 2010;19:4313-8. [PMC free article: PMC2957323] [PubMed: 20719861]
• Rodriguez S, Gaunt TR, Guo Y, Zheng J, Barnes MR, Tang W, Danish F, Johnson A, Castillo BA, Li YR, Hakonarson H, Buxbaum SG, Palmer T, Tsai MY, Lange LA, Ebrahim S, Davey Smith G, Lawlor DA, Folsom AR, Hoogeveen R, Reiner A, Keating B, Day IN. Lipids, obesity and gallbladder disease in women: insights from genetic studies using the cardiovascular gene-centric 50K SNP array. Eur J Hum Genet. 2016;24:106-12. [PMC free article: PMC4681116] [PubMed: 25920552]
• Salen G, Horak I, Rothkopf M, Cohen JL, Speck J, Tint GS, Shore V, Dayal B, Chen T, Shefer S. Lethal atherosclerosis associated with abnormal plasma and tissue sterol composition in sitosterolemia with xanthomatosis. J Lipid Res. 1985;26:1126-33. [PubMed: 4067433]
• Salen G, Starc T, Sisk CM, Patel SB. Intestinal cholesterol absorption inhibitor ezetimibe added to cholestyramine for sitosterolemia and xanthomatosis. Gastroenterology. 2006;130:1853-7. [PubMed: 16697747]
• Sehayek E, Yu HJ, von Bergmann K, Lutjohann D, Stoffel M, Duncan EM, Garcia-Naveda L, Salit J, Blundell ML, Friedman JM, Breslow JL. Phytosterolemia on the island of Kosrae: founder effect for a novel ABCG8 mutation results in high carrier rate and increased plasma plant sterol levels. J Lipid Res. 2004;45:1608-13. [PubMed: 15210841]
• Shulman RS, Bhattacharyya AK, Connor WE, Fredrickson DS. Beta-sitosterolemia and xanthomatosis. N Engl J Med. 1976;294:482-3. [PubMed: 1246333]
• Solcà C, Stanga Z, Pandit B, Diem P, Greeve J, Patel SB. Sitosterolaemia in Switzerland: molecular genetics links the US Amish-Mennonites to their European roots. Clin Genet. 2005;68:174-8. [PMC free article: PMC1201539] [PubMed: 15996216]
• Steiner R. Sitosterolemia. Medscape - WebMD Health Professional Network. Available online; free registration required. 2011. Accessed 8-24-22.
• Su X, Shao Y, Lin Y, Zhao X, Zhang W, Jiang M, Huang Y, Zeng C, Liu L, Li X. Clinical features, molecular characteristics, and treatments of a Chinese girl with sitosterolemia: a case report and literature review. J Clin Lipidol. 2019;13:246-50. [PubMed: 30782472]
• Su Y, Wang Z, Yang H, Cao L, Liu F, Bai X, Ruan C. Clinical and molecular genetic analysis of a family with sitosterolemia and co-existing erythrocyte and platelet abnormalities. Haematologica. 2006;91:1392-5. [PubMed: 17018391]
• Sun W, Zhang T, Zhang X, Wang J, Chen Y, Long Y, Zhang G, Wang Y, Fang T, Chen M. Compound heterozygous mutations in ABCG5 or ABCG8 causing Chinese familial sitosterolemia. J Gene Med. 2020;22:e3185. [PubMed: 32166861]
• Tada H, Kawashiri MA, Okada H, Endo S, Toyoshima Y, Konno T, Nohara A, Inazu A, Takao A, Mabuchi H, Yamagishi M, Hayashi K. A rare coincidence of sitosterolemia and familial Mediterranean fever identified by whole exome sequencing. J Atheroscler Thromb. 2016;23:884-90. [PMC free article: PMC7399263] [PubMed: 27170062]
• Tada H, Nohara A, Inazu A, Sakuma N, Mabuchi H, Kawashiri MA. Sitosterolemia, hypercholesterolemia, and coronary artery disease. J Atheroscler Thromb. 2018;25:783-9. [PMC free article: PMC6143779] [PubMed: 30033951]
• Tada H, Okada H, Nomura A, Yashiro S, Nohara A, Ishigaki Y, Takamura M, Kawashiri MA. Rare and deleterious mutations in ABCG5/ABCG8 genes contribute to mimicking and worsening of familial hypercholesterolemia phenotype. Circ J. 2019;83:1917-24. [PubMed: 31327807]
• Togo M, Hashimoto Y, Iso-O N, Kurano M, Hara M, Kadowaki T, Koike K, Tsukamoto K. Identification of a novel mutation for phytosterolemia. Genetic analyses of 2 cases. Clin Chim Acta. 2009;401:165-9. [PubMed: 19111681]
• Triggs-Raine B, Dyck T, Boycott KM, Innes AM, Ober C, Parboosingh JS, Botkin A, Greenberg CR, Spriggs EL. Development of a diagnostic DNA chip to screen for 30 autosomal recessive disorders in the Hutterite population. Mol Genet Genomic Med. 2016;4:312-21. [PMC free article: PMC4867565] [PubMed: 27247959]
• Tsubakio-Yamamoto K, Nishida M, Nakagawa-Toyama Y, Masuda D, Ohama T, Yamashita S. Current therapy for patients with sitosterolemia--effect of ezetimibe on plant sterol metabolism. J Atheroscler Thromb. 2010;17:891-900. [PubMed: 20543520]
• Veit L, Allegri Machado G, Burer C, Speer O, Haberle J. Sitosterolemia-10 years observation in two sisters. JIMD Rep. 2019;48:4-10. [PMC free article: PMC6607017] [PubMed: 31392106]
• von Bergmann K, Sudhop T, Lütjohann D. Cholesterol and plant sterol absorption: recent insights. Am J Cardiol. 2005;96:10D-14D. [PubMed: 15992510]
• Wang G, Wang Z, Liang J, Cao L, Bai X, Ruan C. A phytosterolemia patient presenting exclusively with macrothrombocytopenia and stomatocytic hemolysis. Acta Haematol. 2011;126:95-8. [PubMed: 21576934]
• Wang J, Joy T, Mymin D, Frohlich J, Hegele RA. Phenotypic heterogeneity of sitosterolemia. J Lipid Res. 2004;45:2361-7. [PubMed: 15375183]
• Wang Y, Guo YL, Dong QT, Li JJ. Severe aortic valve stenosis in a 14-year-old boy with sitosterolemia. J Clin Lipidol. 2019;13:49-53. [PubMed: 30528907]
• Wang Z, Cao L, Su Y, Wang G, Wang R, Yu Z, Bai X, Ruan C. Specific macrothrombocytopenia/hemolytic anemia associated with sitosterolemia. Am J Hematol. 2014;89:320-4. [PubMed: 24166850]
• Watts GF, Mitchell WD. Clinical and metabolic findings in a patient with phytosterolaemia. Ann Clin Biochem. 1992;29:231-6. [PubMed: 1626933]
• Wilund KR, Yu L, Xu F, Vega GL, Grundy SM, Cohen JC, Hobbs HH. No association between plasma levels of plant sterols and atherosclerosis in mice and men. Arterioscler Thromb Vasc Biol. 2004;24:2326-32. [PubMed: 15514206]
• Yagasaki H, Nakane T, Toda T, Kobayashi K, Aoyama K, Ichikawa T, Sugita K. Carotid intima media thickness in a girl with sitosterolemia carrying a homozygous mutation in the ABCG5 gene. J Pediatr Endocrinol Metab. 2017;30:1007-11. [PubMed: 28771437]
• Zheng J, Ma J, Wu RH, Zhang X, Su Y, Zhang R, Zhang LQ. Unusual presentations of sitosterolemia limited to hematological abnormalities: a report of four cases presenting with stomatocytic anemia and thrombocytopenia with macrothrombocytes. Am J Hematol. 2019;94:E124-E127. [PubMed: 30697800]