Sitosterolaemia

Phytosterolaemia due to biallelic deficiency of the ABCG5/ABCG8 sterol transporter

Literature and regulatory information updated: 31 October 2026.

0. Initial Reference Table

1. Introduction

1.1. Definition and scope

Sitosterolaemia is an autosomal recessive disorder of sterol transport in which loss of function of the ABCG5/ABCG8 heterodimer (sterolin-1/sterolin-2) removes the barrier that normally prevents retention of sterols of plant and shellfish origin. The result is intestinal hyperabsorption of all dietary sterols, including cholesterol, and reduced biliary excretion, with accumulation of sitosterol, campesterol and stigmasterol in plasma and tissues [1, 6, 8]. The clinical expression ranges from the absence of signs to tendon and tuberous xanthomatosis in childhood, early coronary and aortic valve atherosclerosis with sudden death, and a haematological picture of haemolytic anaemia with stomatocytes and macrothrombocytopenia that may be the only manifestation [1, 4, 12].

This article covers a single entity with two genes. Online Mendelian Inheritance in Man (OMIM) separates sitosterolaemia 1 (STSL1, #210250), caused by biallelic variants in ABCG8, from sitosterolaemia 2 (STSL2, #618666), caused by biallelic variants in ABCG5; the phenotype is the same and the separation is only genetic [6, 7]. Orphanet keeps a single entity (ORPHA:2882), which includes both genes [2]. The 2020 European Atherosclerosis Society (EAS) table of rare dyslipidaemias still assigns number 210250 to both genes, as it predates the creation of 618666 [21]. Gallbladder disease 4 (GBD4, #611465) is a susceptibility association with gallstones conferred by a common ABCG8 variant and does not belong to the Mendelian spectrum of sitosterolaemia [11]. Sitosterolaemia does not constitute a syndromic class with distinct clinical subtypes; the useful grouping is that of the phenocopies of familial hypercholesterolaemia (FH), in which it is included alongside autosomal recessive hypercholesterolaemia and lysosomal acid lipase deficiency [21, 27, 28].

1.2. Nomenclature

The name "β-sitosterolaemia" was given by those who described the disease, because β-sitosterol is the most abundant plant sterol in the diet and in patients' plasma [1, 29]. "Phytosterolaemia" is the synonym most used in the European literature and that of Orphanet; "xenosterolaemia" emphasises that the accumulated sterols are not synthesised by the body [2, 5]. The proteins are known as sterolin-1 (ABCG5) and sterolin-2 (ABCG8) [8]. The designation "Mediterranean stomatocytosis/macrothrombocytopenia", used since 1969–1975 for Italian and Greek immigrants in Australia with stomatocytosis, splenomegaly and large platelets, was reinterpreted in 2005 as the haematological presentation of phytosterolaemia; some of the Italian families with macrothrombocytopenia classified as "Mediterranean" instead had the dominant GP1BA variant p.Ala156Val (historical numbering of the mature protein, = NM_000173.7:c.515C>T p.(Ala172Val)) (monoallelic Bernard-Soulier syndrome), so the historical term should not be used as a diagnosis [4, 6, 30].

1.3. Historical milestones

In 1974, Bhattacharyya and Connor described two sisters of German and German-Swiss ancestry, intellectually normal, with extensive tendon xanthomas and normal plasma cholesterol. β-sitosterol was 27.1 and 17.7 mg/100 mL, campesterol 9.7 and 8.2 mg/100 mL, and plant sterols accounted for 15.6% and 11.3% of plasma sterols, carried mainly in low-density lipoproteins (LDL; 76% and 83%). Absorption of β-sitosterol was about 24% and 28%, versus less than 5% in controls, and the xanthomas contained 36.7 and 4.0 mg of plant sterols per gram. With unaffected parents, the authors proposed a recessively transmitted lipid storage disease [31]. In 1976, Shulman and colleagues showed that a diet rich in vegetable oils, then recommended to increase polyunsaturated fat, worsened the disease [6].

The following years added the systemic manifestations. Miettinen described in 1980 a patient with hypersplenism and atherosclerosis requiring triple coronary artery bypass surgery at 29 years, initially diagnosed as FH without raised cholesterol, in whom up to 30% of serum and biliary sterols were plant sterols; Wang and colleagues (1981) reported a Chinese man with xanthomatosis, severe coronary disease and chronic haemolytic anaemia with stomatocytes [6]. Kwiterovich and colleagues found the disease among the Amish of Lancaster County, Pennsylvania, and Beaty and colleagues (1986) studied 254 relatives of a 13-year-old Amish proband who died suddenly of advanced coronary atherosclerosis, confirming autosomal recessive inheritance by segregation analysis [6]. Nguyen and colleagues (1990) showed that hepatic cholesterol synthesis is greatly reduced in sitosterolaemia, with decreased 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase and a compensatory increase in receptor-mediated LDL uptake, which explains the poor response to statins [6].

The STSL locus was mapped to 2p21 in 1998 and narrowed to an interval of about 2 centimorgans, with founder effects among Amish/Mennonites, Finns/Norwegians and Japanese [7, 29]. In December 2000, Berge and colleagues identified seven mutations in two adjacent, oppositely oriented genes of the adenosine triphosphate (ATP)-binding cassette (ABC) transporter family in nine patients, six in ABCG8 and one in ABCG5 [32]. In January 2001, Lee and colleagues described ABCG5 mutations in nine unrelated families, and in August of the same year Lu and colleagues showed that the remaining 25 families had mutations in ABCG8, located less than 400 base pairs from ABCG5, and that both genes are indispensable [8, 29]. In 2004, Graf and colleagues showed that the causal missense variants prevent heterodimerisation or trafficking of the heterodimer to the membrane [33]. In the same year, the randomised trial demonstrating reduction of plant sterols with ezetimibe was published [34]; this drug, authorised in the USA in October 2002 and in Portugal in April 2003, has a specific indication for homozygous familial sitosterolaemia in the current labels [22, 23]. In 2005, Rees and colleagues linked stomatocytosis with macrothrombocytopenia to phytosterolaemia [4]. In 2021, the Japan Atherosclerosis Society published the first formal diagnostic criteria [13], and in 2026 a committee of the Japanese Ministry of Health published the catalogue of variants and clinical features of 155 patients described in the literature [12].

2. Molecular Genetics and Pathophysiology

2.1. The genes and the transporter

ABCG5 and ABCG8 lie at 2p21, in opposite orientation and separated by less than 400 base pairs, sharing a promoter region; each has 13 exons [3, 8, 35, 36]. They encode half-transporters of the G subfamily of ABC transporters, with one nucleotide-binding domain and only six of the twelve transmembrane segments usual in full ABC transporters; the functional transporter is an obligate ABCG5/ABCG8 heterodimer [1, 3]. Expression is highest in the enterocyte and the hepatocyte, where the heterodimer pumps sterols into the intestinal lumen and into bile [1, 32]. Maturation requires glycosylation: ABCG8 is glycosylated at asparagine 619, required for trafficking of the heterodimer, and ABCG5 at asparagines 585 and 592 [33]. The MANE (Matched Annotation from NCBI and EMBL-EBI) reference transcripts are NM_022436.3 (ABCG5) and NM_022437.3 (ABCG8); many reports use the .2 versions, with the same c. numbering for the variants cited here, described according to Human Genome Variation Society (HGVS) nomenclature [3, 37].

2.2. Physiology of sterol absorption

A Western diet contains about 250–500 mg/day of cholesterol and 200–400 mg/day of non-cholesterol sterols [29]; in the original work, usual intake of plant sterols was estimated at 150–250 mg/day [31]. Cholesterol and plant sterols enter the enterocyte via the Niemann-Pick C1-like 1 (NPC1L1) transporter, the target of ezetimibe. On average, the intestine absorbs about 50% of dietary cholesterol, with individual variation from 20% to 80% [20], whereas less than 5% of plant sterols are absorbed and less than 1% retained, because the ABCG5/ABCG8 heterodimer actively returns them to the lumen; the liver completes the selection by preferentially excreting them into bile [13, 20, 29]. Consequently, in healthy people, cholesterol accounts for more than 99% of circulating sterols and plant sterols are about 100 times lower than cholesterol [1, 38]. Plant sterols differ from cholesterol only by an ethyl group (sitosterol, stigmasterol) or a methyl group (campesterol) at carbon 24 of the side chain [39].

The liver is the predominant organ in the balance of non-cholesterol sterols. In a Finnish patient with cirrhosis and incidentally discovered sitosterolaemia, orthotopic liver transplantation lowered plant sterols to values only slightly above those of the heterozygous father, although the intestinal defect persisted [40].

2.3. Consequences of loss of function

Without the heterodimer, sitosterol absorption rises to 24–28%, versus less than 5% in healthy people, and biliary sterol excretion falls; sitosterol, campesterol, stigmasterol, shellfish sterols and plant stanols (sitostanol, campestanol) accumulate and are incorporated into lipoproteins, mainly LDL, and into tissues [1, 21, 24, 31]. The increased delivery of cholesterol to the liver suppresses endogenous synthesis: HMG-CoA reductase activity and messenger ribonucleic acid (mRNA) are greatly reduced and receptor-mediated LDL uptake is increased [6]. This suppression explains why statins have little effect on plant sterols and why plasma cholesterol depends strongly on dietary cholesterol and sterols [13, 20, 41]. Ezetimibe, by blocking NPC1L1, acts upstream of the defect and reduces the entry of all sterols [42].

Plant sterols incorporated into erythrocyte and platelet membranes alter membrane fluidity and structure, giving rise to stomatocytosis, haemolysis and macrothrombocytopenia with an abnormal platelet response to ristocetin [4, 5]. In erythrocytes from Indian patients with transfusion-dependent haemolytic anaemia, increased intracellular calcium, exaggerated influx under osmotic stress, increased reactive oxygen species and a persistent population of overhydrated stomatocytes were demonstrated, which persisted despite the fall in sterols with ezetimibe [43]. In the Abcg5/Abcg8-deficient mouse, accumulation of plant sterols reduced adrenal cholesterol by 91% without a compensatory response, an effect reversed by ezetimibe; stigmasterol, but not sitosterol, inhibited the sterol regulatory element-binding protein 2 (SREBP-2) pathway in adrenal cells [6].

Homeostasis changes with age. In the Hutterite kindred studied over two decades, baseline cholesterol and sitosterol values were inversely proportional to age, as was the percentage response to ezetimibe; the authors proposed a homeostatic shift at puberty, with inhibition of SREBP-2, lower cholesterol synthesis, lower PCSK9 (proprotein convertase subtilisin/kexin type 9) and higher LDL receptor activity [44]. This observation helps to explain the marked hypercholesterolaemia of childhood, sometimes in the range of homozygous FH, and the spontaneous normalisation of cholesterol in many adults [1, 13].

2.4. Plant sterols or LDL-C as the cause of atherosclerosis

Plant sterols accumulate in plaques, but a causal relationship between circulating sitosterol and atherosclerotic cardiovascular disease has not been demonstrated [13]. In the G5G8−/− mouse, with plant sterols more than 20 times above normal, the aortic lesion area did not differ from that of controls, and among 2542 adults aged 30–67 years in the Dallas Heart Study coronary calcium was associated with cholesterol, but not with sitosterol or campesterol [14]. In France, five patients referred for suspected homozygous FH, with β-sitosterol and campesterol 15–30 times above normal, total cholesterol above 450 mg/dL and LDL-C above 350 mg/dL at diagnosis, had no significant subclinical atherosclerosis at 32, 27, 29, 11 and 11 years, after cholesterol had been lowered with diet and drugs, although plant sterols remained raised [45]. Paediatric cases in which xanthomas progress and regress in step with LDL-C point in the same direction, and the Japanese guideline treats LDL-C, and not sitosterol, as the main atherogenic factor and therapeutic target [13, 46]. In patients' LDL particles, the abnormally high phytosterol content may nevertheless increase atherogenic potential, an unproven hypothesis [5].

2.5. Variant spectrum

GeneReviews attributed, in 2020, 42% of cases to ABCG5 and 58% to ABCG8, with detection of more than 95% of pathogenic variants by sequencing and no deletions or duplications described up to that date [1]. The 2026 Japanese catalogue gathered 155 patients from 133 families described between 2002 and 2024: 47 homozygous and 59 compound heterozygous for ABCG5, 21 homozygous and 27 compound heterozygous for ABCG8, and one double heterozygote ABCG5 + ABCG8; 50 ABCG5 variants and 51 ABCG8 variants were considered pathogenic, with 3 and 1 variants of uncertain significance (VUS) [12]. Truncating variants predominate and are distributed along both genes [3, 12]. Copy number variations (CNV) have since been described: a large deletion of exon 3 of ABCG5 in a 75-year-old Japanese-Canadian patient and a homozygous deletion of exons 2 and 3 of ABCG8 in a 6-year-old Turkish girl [12, 47].

The geographical distribution is uneven. In Europeans ABCG8 predominates, and in Chinese, Japanese and Indian patients, who represented about 20% of known cases in 2017, ABCG5 predominates [1, 3]. In the review of 131 Chinese cases, ABCG5 accounted for 77.1% [48]; in a Vietnamese paediatric series, 10 of 14 patients [49]; and in a Beijing paediatric series, 10 of 12 [18]. In the Ibero-American series of 16 cases, 15 had biallelic ABCG8 variants, seven homozygous and eight compound heterozygous, and one had a homozygous ABCG5 variant [50]. The genotype table of that series lists ten distinct ABCG8 variants (five nonsense, one frameshift and four missense) and one ABCG5 frameshift variant; ABCG8 p.(Trp361Ter), p.(Tyr492Ter) and p.(Tyr658Ter) occurred in two or more countries, and p.(Trp229Ter) had no ClinVar entry at the time of publication [30, 50]. The authors used transcript versions NM_022436.2 and NM_022437.2; the c. and p. numbering coincides with that of the MANE transcripts NM_022436.3 and NM_022437.3 [37, 50].

Some sources record the ABCG5 variant c.751C>T with the wrong nucleotide change; the correct form, confirmed in VariantValidator and ClinVar, is c.751C>T p.(Gln251Ter) [30, 37]. Review tables that include ABCG8 p.(Asp19His) among the causal variants confuse a common susceptibility variant with a pathogenic variant [11, 30].

2.6. Mechanism of missense variants

Thirteen causal missense variants expressed in Chinese hamster ovary cells all reduced trafficking of the heterodimer from the endoplasmic reticulum to the Golgi apparatus, and most prevented the formation of stable heterodimers [33]. The mechanism is therefore loss of function, with no dominant-negative effect described [1, 20].

2.7. Genotype-phenotype correlation, penetrance and expressivity

GeneReviews identified no genotype-phenotype correlations [1]. In the 2026 catalogue, mean serum sitosterol varied between variants, from 1.5 ± 1.2 mg/dL with ABCG8 NM_022437.3:c.1715T>C p.(Leu572Pro) to 36.6 ± 30.1 mg/dL with ABCG5 NM_022436.3:c.1256G>A p.(Arg419His), but without correlation between sitosterol and total cholesterol or LDL-C, and with a scatter that precludes individual predictions [12]. Intrafamilial variability is the rule: in a consanguineous family, three siblings and a cousin with the same genotype included one with abdominal pain, anaemia, xanthomas and early cardiac death, while the others had only raised cholesterol and plant sterols; in another family, the proband's mother and brother were homozygous for the same ABCG5 variant and had raised sitosterol, but only the 6-year-old proband had xanthomas [1]. In the Ibero-American series, carriers of two ABCG8 null variants (p.(Trp361Ter), p.(Tyr492Ter), p.(Tyr658Ter)) had earlier onset, mean LDL-C above 400 mg/dL, higher β-sitosterol and more xanthomas and haemolytic anaemia, combinations with a missense variant, such as p.(Leu533Pro), had slightly less severe biochemical profiles, and the patient homozygous for the ABCG5 frameshift variant had a severe phenotype; the series has 16 patients, and the comparison is descriptive, without statistical analysis [50]. In the Portuguese family homozygous for ABCG8 p.(Tyr658Ter), one member had xanthomas and haemolytic anaemia, with clinical diagnosis at 4 years and β-sitosterol of 511 µmol/L, and the other had xanthomas without anaemia, with clinical diagnosis at 28 years and β-sitosterol of 224 µmol/L [50]. Biochemical penetrance (raised plant sterols) is complete in biallelic carriers who ingest plant sterols, but clinical penetrance is incomplete and depends on diet and age: among the 21 Hutterite homozygotes identified mainly by screening, most were asymptomatic and without stigmata [44].

2.8. Heterozygotes, double heterozygosity and modifiers

Obligate heterozygotes are clinically healthy, but some have slightly raised plant sterols, which rise with plant sterol supplementation [1, 3]. In Kosrae, Micronesia, the 150 carriers of an ABCG8 founder variant among 1090 genotyped adults had campesterol 55% and sitosterol 30% higher than non-carriers, with no difference in total cholesterol [15]. In a case-control study of coronary artery disease (CAD) with 29,321 cases and 357,326 controls, rare loss-of-function variants occurred in about 0.1% of individuals in each gene; heterozygosity in ABCG5 was associated with LDL-C 25 mg/dL higher (95% confidence interval, 95% CI, 14–35) and an odds ratio (OR) for CAD of 2.06 (95% CI 1.27–3.35), with no association for ABCG8 [10]. In the Netherlands, among 3031 patients with clinical FH, 1.48% had pathogenic or likely pathogenic variants in ABCG5 and 0.96% in ABCG8, with lower LDL-C than carriers of LDLR variants (6.2 ± 1.7 versus 7.2 ± 1.7 mmol/L) and incomplete segregation with LDL-C in families [53]. In Japan, 8% of 487 patients with clinical FH had a deleterious variant in ABCG5/ABCG8 without an FH variant, 0.6% had biallelic sitosterolaemia, and 4% were oligogenic (FH + ABCG5/ABCG8), with higher LDL-C than the monogenic patients [54]. In the Portuguese Familial Hypercholesterolaemia Study, analysis of the five phenocopy genes in 225 index cases with clinical FH and no variant in the FH genes found a heterozygous loss-of-function variant in ABCG5 in 5 (2.2%) and in ABCG8 in 6 (2.7%), and a heterozygous VUS in ABCG5 in 18 (8.0%) and in ABCG8 in 14 (6.2%); mean LDL-C in carriers of heterozygous variants in the phenocopy genes was lower than in patients with confirmed FH (children, 168.6 ± 21.6 versus 217.1 ± 49.7 mg/dL; adults, 215.1 ± 67.5 versus 268.2 ± 96.6 mg/dL) and did not differ from that of the other patients without a variant, and some missense variants of ABCG5/ABCG8 did not fully segregate with LDL-C in families [55]. The common polymorphism rs4299376, at the ABCG5/ABCG8 locus (risk allele G, beta coefficient of 0.071 per allele according to the Global Lipids Genetics Consortium), is one of the six polymorphisms in the polygenic LDL-C genetic risk score validated in the Portuguese population and applied to cases of clinical FH without a monogenic variant [51]. In hypercholesterolaemic patients with a heterozygous variant, the combination of atorvastatin 10 mg with ezetimibe 10 mg achieved LDL-C of 72 ± 26 mg/dL versus 87 ± 29 mg/dL in patients without a variant [6].

Cases of double heterozygosity have been described: a 1-year-old Japanese girl with LDL-C of 453 mg/dL and intertriginous xanthomas during breastfeeding, carrying ABCG5 NM_022436.3:c.1166G>A p.(Arg389His) and ABCG8 NM_022437.3:c.1285A>C p.(Met429Leu), with sitosterol of 15.9 µg/mL and confirmed segregation [9], and two Australian sisters with ABCG5 NM_022436.3:c.1336C>T p.(Arg446Ter) and ABCG8 p.(Glu423Asp) (published protein designation; VUS; the corresponding ClinVar entry is NM_022437.3:c.1269G>T p.(Glu423Asp), of uncertain significance), moderately raised sterols and premature CAD on imaging [30, 56]. The same Australian series described simple heterozygotes for ABCG5 NM_022436.3:c.1166G>A p.(Arg389His) with mild phytosterolaemia and CAD on imaging [56]. These observations support a codominant or polygenic effect of ABCG5/ABCG8 on LDL-C and coronary risk, distinct from the recessive disease [27, 57, 58].

2.9. Allelic disorders

GeneReviews records no Mendelian phenotypes, other than sitosterolaemia, associated with biallelic variants in ABCG5 or ABCG8 [1]. Outside the Mendelian spectrum, the common variant ABCG8 c.55G>C p.(Asp19His) (rs11887534) confers susceptibility to gallstones, mainly cholesterol stones: in a German genome-wide association study, the odds ratio was 2.2 in heterozygotes and 7.1 in homozygotes for the His allele (GBD4, #611465) [11]. Genome-wide association studies also link the ABCG5/ABCG8 loci to LDL-C and coronary disease in the general population [13]; ABCG8 is among the more than 160 common variant loci associated with CAD and myocardial infarction, each with a small individual effect [59]. On the absorption side, heterozygous loss-of-function variants in NPC1L1, the target of ezetimibe, occur in about 1 in 150 people, lower LDL-C and are associated with a 53% lower CAD risk, which provides a genetic rationale for inhibiting intestinal sterol absorption [59].

3. Clinical Spectrum and Manifestations by System

3.1. Overview

The clinical expression ranges from absence of signs, frequent in siblings identified by screening, to xanthomas in early childhood, early atherosclerosis with sudden death and isolated haematological pictures [1, 60]. GeneReviews counted in 2020 about 110 individuals with biallelic variants described in 40 publications [1]. The 2026 Japanese catalogue, which gathers the reports from 2002 to 2024, gives the best available estimate of the frequency of manifestations, with the bias inherent in a series of published cases: among 155 patients, 62.6% were women, the median age was 14 years (interquartile range 8–26), xanthomas were present in 69.2% (99/143), ischaemic heart disease in 14.2% (14/98), other atherosclerotic changes in 13.2%, valve disease in 14.2% (11/77) and haematological changes in 57.9% (81/140), divided into anaemia with thrombocytopenia (33.6%), isolated anaemia (7.1%) and isolated thrombocytopenia (17.1%) [12]. Median serum sitosterol was 20.3 mg/dL (8.2–28.5), median total cholesterol 354 mg/dL and median LDL-C 286 mg/dL, without correlation between sitosterol and cholesterol values [12]. In the review of 131 Chinese cases, xanthomas, hypercholesterolaemia and raised LDL-C occurred in 82.4% each, splenomegaly and thrombocytopenia in 32.1% each and anaemia in 30.5%; hypercholesterolaemia was more frequent in children and haematological changes and organ damage in adults [48]. In the Ibero-American series of 16 molecularly confirmed patients (12 index cases and 4 relatives), all had markedly raised LDL-C and an initial clinical diagnosis of heterozygous or homozygous FH; 12 (75%) were clinically diagnosed in childhood, but only 8 (6 index cases and 2 relatives) had a genetic diagnosis at that age, and in 68% the genetic diagnosis came between 5 and 30 years after the clinical one [50]. β-sitosterol, measured in 10 of the 16 patients by gas or liquid chromatography coupled to mass spectrometry and at different points in the course, ranged from 39 to 511 µmol/L, always above the reference value of 15 µmol/L used by the authors, with three patients already on treatment [50].

The differences between series reflect the age at recruitment (paediatric cohorts capture the hypercholesterolaemic phase, haematological ones capture adults), the referral route (lipid clinics, haematology, FH screening programmes) and access to sterol measurement, and should not be read as population frequencies [12, 18, 49, 50, 61].

3.2. Skin, tendons and eyes

Xanthomas are the most common presentation in the child. They are tendinous (Achilles tendon, extensor tendons, patellar tendons) and tuberous, typically located on the heels, knees, elbows, wrists and buttocks [1, 18, 49]. In the infant, they appear as intertriginous or linear xanthomas in the ankle creases, described as early as 4–6 months of life, at 1–2 years, and at 4 and 6 years [1, 9, 18, 19]. The severity of tendon xanthomas tends to be greater than in heterozygous FH with similar or higher LDL-C [13]. Palpebral xanthelasmas [39, 62], corneal arcus and lipid keratopathy of the cornea in a 9-year-old girl [63] and in a 7-year-old girl whose keratopathy was surgically removed before diagnosis [64], and an associated necrobiotic xanthogranuloma [65] have also been described. Xanthomas appear at ages at which heterozygous FH rarely produces them, and a 1-year-old girl with xanthomas on the ankle and wrist illustrates the Japanese guideline [13].

3.3. Plasma lipids

Plasma cholesterol is not necessarily raised; patients are very sensitive to dietary cholesterol and sterols and become markedly hypercholesterolaemic on a cholesterol-rich diet [20]. In childhood, cholesterol may reach the range of homozygous FH: in four Vietnamese children LDL-C exceeded 13 mmol/L [49], and in the Beijing series total cholesterol ranged from 7.33 to 76.92 mmol/L [18]. In the Hutterites, baseline cholesterol values decreased with age, and in many adults cholesterol normalises [1, 44]. LDL-C varies widely with recent intake of plant sterols [13]. In breastfed infants, breast milk contains phytosterols and cholesterol, and skin xanthomas with LDL-C similar to that of homozygous FH have been described, which regressed only with weaning despite sitosterol remaining raised; conversely, a Romanian infant became symptomatic only after weaning from exclusive breast milk [3, 7, 13]. A transient "breastfed infant hypercholesterolaemia", without xanthomas, has also been described in ABCG5 heterozygotes [13]. Triglycerides and high-density lipoprotein (HDL) cholesterol are generally normal [18, 39].

3.4. Cardiovascular system

GeneReviews gathered in 2020 ten individuals with atherosclerosis with onset between 5 and 33 years, with or without sudden death, and aortic valve involvement, infarction and angina [1]. The reference cases include a 13-year-old Amish boy who died suddenly of advanced coronary atherosclerosis [6], a 19-year-old man with acute myocardial infarction and a child homozygous for an ABCG8 nonsense variant with aortic xanthomatosis and occlusion of the coronary ostia [3], and a 5-year-old girl whose aortic valve, dissected post mortem, showed severe atherosclerosis with occluded coronary ostia [21]. The incidence of coronary disease is unknown because of the limited number of cases [1]. Among the 14 Brazilian patients identified in an FH screening programme, with a mean age of 37 years, 78.6% (all the adults) had clinical or subclinical atherosclerotic cardiovascular disease [61]. By contrast, five treated French patients had no significant subclinical atherosclerosis up to 32 years [45], and most of the 21 treated Hutterite homozygotes were asymptomatic [44]. Aortic and mitral valve disease is a feature that distinguishes it from heterozygous FH: a Swiss patient homozygous for ABCG8 p.(Gly574Arg) had mitral and aortic valve disease [6], and a French patient needed a mechanical aortic valve prosthesis at 50 years for severe aortic stenosis [5].

3.5. Blood and spleen

Accumulation of plant sterols in blood cell membranes produces haemolytic anaemia with stomatocytes, thrombocytopenia with large or giant platelets (macrothrombocytopenia) and splenomegaly; these changes may be the initial presentation or the only manifestation [1, 4, 66]. In GeneReviews, haemoglobin in anaemic patients ranged from 76 to 109 g/L and platelets from 12 to 82 × 10⁹/L [1]. In the five families of Rees and colleagues, all patients had mild haemolysis with reticulocytosis, mild hyperbilirubinaemia, marked stomatocytosis, very large platelets with increased mean platelet volume, splenomegaly and short stature; some had abdominal pain and a bleeding tendency, and none, all under 30 years, had cardiovascular disease [4, 6]. In a Chinese series of 13 patients from 8 families, the blood film showed large platelets surrounded by a ring of vacuoles and stomatocytes; all had previously received diagnoses of immune thrombocytopenia (ITP), Evans syndrome or secondary ITP, with a mean delay of 28.8 years [67]. A 2019 review estimated haematological changes in 25–35% of patients, associated with the main manifestations in 70% of cases, and warned of the harmful treatments resulting from a misdiagnosis of ITP [68].

Reports from 2025–2026 confirm this profile in adults. In an Indian series of six adults (median age 40 years), all had anaemia, thrombocytopenia, splenomegaly, stomatocytes and giant platelets, with previous diagnoses of ITP, iron deficiency, megaloblastic anaemia or Evans syndrome; three had tendon xanthomas and one premature CAD [69]. In another Indian series, seven patients with a median age of 15 years all had anaemia and splenomegaly, six had thrombocytopenia and none had tendon xanthomas or evident dyslipidaemia [70]. Four Indian patients with haemolytic anaemia and recurrent transfusions continued to have haemolysis despite the fall in sterols with ezetimibe [43]. An 18-year-old Australian girl presented with menorrhagia due to macrothrombocytopenia and compensated haemolytic anaemia [41]. The frequency of haematological changes differs between populations and ages: in the Vietnamese paediatric series only 1 of 14 children had anaemia and none had thrombocytopenia [49], whereas 83% of the Brazilian patients identified in FH screening had haematological changes [61].

3.6. Liver, joints and other manifestations

Liver disease may be the presentation: a patient with "chronic active hepatitis" and cirrhosis had undiagnosed sitosterolaemia [40], and raised transaminases were associated with the disease in a Turkish screening for chronic thrombocytopenia [71]. In the Beijing series, one child had transaminases of 213 and 245 U/L at diagnosis [18]. Arthritis and arthralgia occur occasionally [1, 49]; a Japanese case of recurrent arthritis also had familial Mediterranean fever, identified by exome sequencing, a warning about concomitant recessive diseases in consanguineous families [13]. Spinal cord compression with paraplegia due to xanthomas in a normocholesterolaemic patient [6], a systemic inflammatory picture with histiocytosis that mimicked Takayasu arteritis and a histiocytic tumour in a 30-year-old Finnish man homozygous for ABCG8 p.(Trp361Ter) [72], and coexistence with nephronophthisis due to a homozygous NPHP1 deletion in a Chinese child initially diagnosed with haemophagocytic lymphohistiocytosis [48] have been described. Coexistence with heterozygous FH was described in 2026 [73].

3.7. Natural history and treated disease

There is no population-based natural history study; the data come from case series with publication bias towards severe pictures [12]. Follow-up of 21 Hutterite homozygotes over two decades, almost all identified by family screening and treated with ezetimibe, showed low morbidity relative to the true prevalence [44]. In the treated cohorts, diet and ezetimibe reduced cholesterol, caused xanthomas to regress and normalised haemoglobin in children followed for up to 8 years and 7 months [18]; a Brazilian patient followed for 21 years with diet and ezetimibe had resolution of splenomegaly and thrombocytopenia, stabilisation of xanthomas and no cardiovascular events, although campesterol and β-sitosterol remained above normal [52]. The absence of events in these series does not allow lifetime risk to be estimated.

4. Clinical Recognition and Warning Signs

4.1. In the child with xanthomas or hypercholesterolaemia

Suspicion should arise in the presence of tendon, tuberous or intertriginous xanthomas in the first decade, especially at unusual sites (heels, knees, elbows, buttocks, ankle creases), with normal or only moderately raised cholesterol [1, 20]. Additional warning signs are: childhood hypercholesterolaemia that falls unexpectedly and markedly with a diet low in fat and plant sterols or with a bile acid sequestrant; hypercholesterolaemia that does not respond to statins; absence of hypercholesterolaemia and early coronary disease in the parents, despite a homozygous FH phenotype in the child; and xanthomas more severe than would be expected for the LDL-C [1, 3, 13]. The infant's feeding history is a guide: the phenotype may appear during breastfeeding or with infant formula, or only after weaning, and the disease should be considered even before complementary feeding, because breast milk contains phytosterols [1, 3, 13]. In the Vietnamese series, 13 of 14 children were initially diagnosed with heterozygous or homozygous FH [49], and in the Ibero-American series all index cases had first been diagnosed with FH, with delays of up to 30 years [27, 50].

4.2. In the adult with cardiovascular disease or xanthomas

In the adult, the warning signs are premature coronary disease or aortic stenosis with tendon xanthomas and only mildly raised cholesterol, resistance to statins with a good response to ezetimibe, and the coexistence of xanthomas with haematological changes [5, 39, 74]. The triad of xanthomas, haematological changes and a good response to ezetimibe, with a poor response to statins, is the combination with the highest suggestive value [5]. Thrombocytopenia that appears during statin treatment and is attributed to the drug should prompt consideration of sitosterolaemia [5].

4.3. In the patient with haematological changes

The disease should be sought in the presence of macrothrombocytopenia, stomatocytosis or non-immune haemolytic anaemia of undetermined cause, especially with splenomegaly, and before accepting a diagnosis of chronic refractory ITP, Evans syndrome or inherited thrombocytopenia [1, 67, 68]. In a Turkish multicentre study that measured sitosterol in 100 patients with unexplained chronic thrombocytopenia, non-immune haemolytic anaemia or abnormal red cell morphology, 15 had sitosterol above 15 mg/L, 9 persistently and 7 with final confirmation, a detection rate of 7% in this at-risk population; consanguinity, xanthomas and raised transaminases were associated with the diagnosis, and dyslipidaemia was not always present [71]. Inborn Metabolic Diseases includes sitosterolaemia, with stomatocytes, among the metabolic causes of haemolytic anaemia, and among the metabolic causes of xanthomas in childhood [75]. The peripheral blood film, with stomatocytes and large platelets surrounded by vacuoles, is an inexpensive diagnostic clue [67, 76]. In Scotland, a patient from an island community was recognised through macrothrombocytopenia and haemolytic anaemia, without raised cholesterol [16].

4.4. Other contexts

Contexts of suspicion include chronic liver disease without an apparent cause [40], lipid keratopathy of the cornea in a child [63, 64], incidental detection of ABCG5/ABCG8 variants on an FH panel [56, 61], and membership of founder populations with a known variant (Hutterites, Amish and Mennonites, Kosrae, Scottish islands) [1, 16].

4.5. Emergency signs

Emergencies are chest pain, exertional syncope or an aortic stenosis murmur in a child or adolescent with xanthomas, because infarction and sudden death have been described between 5 and 18 years, especially in untreated patients [1, 5]; severe thrombocytopenia with bleeding (for example, menorrhagia) [41]; and haemolysis requiring transfusion [43].

4.6. Newborn screening

There is no newborn screening for sitosterolaemia; the transporters are abnormal from birth, but the rise in plant sterols occurs only after ingestion of plant foods or formula, and the biochemical diagnosis cannot be excluded before then [1]. There are also no specific guidelines for cascade screening [58].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Diagnostic criteria

GeneReviews does not establish formal criteria: diagnosis rests on markedly raised plasma plant sterols and/or biallelic pathogenic or likely pathogenic variants in ABCG5 or ABCG8 [1]. The only formal criteria published are those of the Japan Atherosclerosis Society and the primary dyslipidaemia committee of the Japanese Ministry of Health (2021) [13].

The Japanese criteria require xanthomas for all categories and therefore do not capture isolated haematological forms or asymptomatic siblings identified by screening; in these cases, diagnosis rests on biochemistry and genotype, as in GeneReviews [1, 13, 70].

5.2. Measurement of plant sterols

Plant sterols (sitosterol, campesterol, stigmasterol; also shellfish sterols and stanols) are not distinguished from cholesterol by routine enzymatic methods, which count them as cholesterol, and require gas chromatography (GC), GC-mass spectrometry (GC-MS), high-performance liquid chromatography (HPLC) or liquid chromatography-tandem mass spectrometry (LC-MS/MS), available only in specialist laboratories [1, 3, 27]. The EAS consensus classifies them as specialist lipid biochemistry, confirmatory of the diagnosis [21].

In untreated sitosterolaemia, sitosterol is 30 to 100 times above normal (10–65 mg/dL); sitosterol above 1 mg/dL is considered diagnostic outside infancy [1]. The cardiogenetics book uses the same threshold, expressed as 0.024 mmol/L [20]. In healthy Japanese people, the reference ranges for sitosterol are 0.99–3.88 µg/mL in men and 1.03–4.45 µg/mL in women [13]. Units vary between laboratories: the Japanese catalogue converts µmol/L to mg/dL by multiplying by 0.04147, so 1 mg/dL corresponds to about 24 µmol/L [12]. In sitosterolaemia, cholesterol accounts for only about 80% of plasma sterols, versus more than 99% in healthy people [3, 38]. The Turkish screening study measured sitosterol after fasting for at least 8 hours and repeated values above 15 mg/L before genetic testing [71]. Cholestanol may also be raised in sitosterolaemia, as occurred in several children in the Beijing series (up to 82.52 µmol/L), which limits its use alone to distinguish CTX [18].

The diagnostic accuracy of sitosterol is high at the extremes and low in an intermediate zone. In a Chinese study of 379 children (38 with sitosterolaemia, 12 heterozygotes, 54 with genetic FH, 50 with an FH-like phenotype and 225 controls), the area under the curve (AUC) for sitosterol was 0.994 (95% CI 0.988–1.000), but fell to 0.653 in the "grey zone" of 17.7–50 µg/mL; a multivariable model with several sterols achieved 0.983 overall and 0.806 in that zone [77]. The 1 mg/dL threshold was set mainly with patient data and may need to be revised with data from heterozygotes and healthy people [12].

5.3. False positives and false negatives

Plasma cholesterol is not diagnostic, because it may be normal [1]. Carriers cannot be reliably identified by sterol measurement [1].

5.4. Molecular testing

Sequencing of ABCG5 and ABCG8 is performed on a multigene dyslipidaemia or hypercholesterolaemia panel that includes deletion and duplication analysis; exome or genome sequencing serves cases in which the disease was not suspected [1, 3, 21]. In Portugal, the eight-gene panel recommended since 2018 by an expert group for the study of FH includes phenocopy genes and identifies sitosterolaemia [27]. Until 2017, the Portuguese Familial Hypercholesterolaemia Study sequenced ABCG5 and ABCG8 by the Sanger method only in a selected subgroup of patients without a variant in LDLR, APOB or PCSK9; the next-generation sequencing panel that the laboratory then adopted combines the three FH genes, the five phenocopy genes (LIPA, APOE, LDLRAP1, ABCG5 and ABCG8) and the six-polymorphism polygenic LDL-C genetic risk score [51]. In Brazil, sequencing of ABCG5/ABCG8 in the 260 FH index cases without a variant in the classic genes found 8 patients with sitosterolaemia (3.1%) [61]. When two heterozygous variants are found, the parents are tested to confirm that they are in trans, and the variant is confirmed from a new DNA dilution [3].

The report should state the gene, the versioned transcript (NM_022436.3 for ABCG5, NM_022437.3 for ABCG8), HGVS c. and p. nomenclature, zygosity and class according to the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) [37, 50]. Disease-adapted ACMG criteria for ABCG5 and ABCG8 were proposed in 2025, based on the Ibero-American series: strict allele frequency thresholds, calculated from prevalence and recessive inheritance; loss-of-function variants as very strong evidence (PVS1); demonstration of the in trans configuration (PM3) according to ClinGen recommendations; in silico predictions calibrated with gene-specific thresholds; raised β-sitosterol as evidence of a specific phenotype (PP4); and exclusion of criteria inapplicable to recessive inheritance or small families [50]. In that series, β-sitosterol served as a surrogate functional assay for missense variants found in trans with a truncating variant, and the ABCG8 variant p.(Leu533Pro) remained a VUS even in trans with p.(Trp536Ter) in a patient with β-sitosterol of 111 µmol/L [50]. Two VUS, or one pathogenic variant and one VUS, neither establish nor exclude the diagnosis; in these cases, plant sterol measurement, family segregation and response to ezetimibe help to decide [1, 74]. In the Portuguese Familial Hypercholesterolaemia Study, five individuals with two heterozygous variants in ABCG5/ABCG8, mostly VUS, did not have raised β-sitosterol by gas chromatography-mass spectrometry, which illustrates the role of measurement in the decision [55].

5.5. Limitations of testing

The proportion of variants detectable by sequencing (more than 95% in GeneReviews) is not the clinical sensitivity of the test [1]. A single pathogenic variant in a patient with a typical phenotype may correspond to a deletion of the other allele, and intragenic deletions of both genes have now been described, which escape sequencing without CNV analysis [1, 12, 47]. In the Beijing series, a child with xanthomas, very high LDL-C, raised phytosterols and a good response to treatment had no variant detected [18]. A negative molecular result therefore does not exclude the disease when plant sterols are clearly raised outside the situations in the previous table. Deep intronic and regulatory region variants are not explored by the usual panels [1, 18].

5.6. Algorithm

The 2020 EAS consensus proposes, in the presence of LDL-C above 10 mmol/L untreated or above 8 mmol/L on treatment, excluding secondary causes (nephrotic syndrome, primary biliary cholangitis, untreated hypothyroidism, anorexia, drugs), assessing xanthomas, corneal arcus and vascular disease, and performing targeted sequencing; biallelic variants in LDLR, APOB, PCSK9 or LDLRAP1 define homozygous FH, biallelic variants in ABCG5/ABCG8 define sitosterolaemia, and biallelic variants in LIPA define atypical lysosomal acid lipase deficiency [21]. The 2023 update of the EAS consensus on homozygous FH requires sitosterolaemia to be excluded before homozygous FH is diagnosed [28].

The algorithm was compiled from the EAS consensus, GeneReviews, the Japanese guideline and the haematological screening studies [1, 13, 21, 71].

5.7. Additional initial assessment

After diagnosis, GeneReviews recommends baseline measurement of plant sterols (β-sitosterol, campesterol) and cholesterol; recording of the size, number and distribution of xanthomas; cardiological assessment for atherosclerosis and valve disease (coronary calcium score by cardiac computed tomography or coronary angiography when necessary); full blood count with film and assessment of haemolysis; liver function (albumin, alanine aminotransferase, ALT, aspartate aminotransferase, AST, alkaline phosphatase, bilirubin); search for splenomegaly, with haematology and gastroenterology assessment if present; assessment of arthralgia and arthritis; and a genetics clinic appointment [1].

5.8. Prenatal and preimplantation diagnosis

With both familial variants identified, prenatal diagnosis and preimplantation genetic testing are technically possible [1]. The European clinical utility gene card considers that genetic testing is essentially confirmatory in a suspected patient, and not predictive or prenatal [3].

6. Differential Diagnosis

6.1. Comparative table

6.2. Sitosterolaemia and familial hypercholesterolaemia

FH is the most frequent misdiagnosis in the published series. The inheritance pattern is the first clue: heterozygous FH has one affected parent, homozygous FH has both, and in sitosterolaemia the parents are usually normolipidaemic, although recessive inheritance does not exclude some family history of hypercholesterolaemia due to heterozygosity [3, 13]. The therapeutic response is the second: sitosterolaemia responds disproportionately to diet, ezetimibe and resins, and little to statins [1, 5]. The 2023 European consensus on homozygous FH includes exclusion of sitosterolaemia in the diagnostic criteria and points out, as a benefit of genetic testing, the avoidance of maximum-dose statins and apheresis when the cause is sitosterolaemia [28]. The 2025–2026 series show the size of the problem: a French woman treated for more than 50 years as homozygous FH, with apheresis and alirocumab, had sitosterolaemia due to compound heterozygosity in ABCG5 [5], and all 16 Ibero-American cases had initially been diagnosed with FH [27, 50]. FH and sitosterolaemia may coexist in the same patient [73], and heterozygous ABCG5/ABCG8 variants aggravate the FH phenotype [54].

6.3. Sitosterolaemia and cerebrotendinous xanthomatosis

Both cause tendon xanthomas in the child and young adult. In CTX, cholesterol is normal or only slightly raised, there is chronic diarrhoea from infancy, juvenile cataracts and, later, neurological disease, and the marker is cholestanol [1, 5, 13]. Absence of neurological involvement and cataracts favours sitosterolaemia [3]. The distinction may fail: cholestanol may be raised in sitosterolaemia [18], and a Brazilian patient with xanthomas and subtle changes on brain magnetic resonance imaging was treated as CTX with chenodeoxycholic acid, without response, until homozygous ABCG8 p.(Trp361Ter) was identified [39].

6.4. Sitosterolaemia and thrombocytopenias with giant platelets

In the presence of congenital macrothrombocytopenia, sitosterolaemia is distinguished from MYH9-related disorders and Bernard-Soulier syndrome by the presence of stomatocytes and haemolysis, splenomegaly, recessive inheritance and, above all, raised plant sterols [4, 67, 78]. MYH9-related disorders have aggregates of MYH9 protein in neutrophils and extra-haematological manifestations (sensorineural deafness, glomerular nephropathy, presenile cataracts, raised liver enzymes) [78]. The most common error is a diagnosis of ITP, which exposes the patient to treatments without benefit and potentially harmful and delays diagnosis by decades [67, 68]. Hereditary haemolytic anaemias enter the differential diagnosis.

7. Treatments and Risk Management Strategies

7.1. Principles and goals

Treatment starts at diagnosis and combines reduction of sterol intake through diet with pharmacological blockade of intestinal absorption [1, 13]. Experience below 2 years is scarce [1]. With treatment, plasma cholesterol and sitosterol fall by 10% to 50% and xanthomas frequently regress [1]. The Japanese guideline adopts the same LDL-C targets as for FH and considers LDL-C, and not sitosterol, the main therapeutic biomarker, because it is the main atherogenic factor [13, 46]. Plant sterols remain the index of adherence and biochemical response, but rarely normalise [45, 49, 52]. The EAS consensus emphasises that treatment differs from that of homozygous FH: apheresis is not needed and the hyperlipidaemia often responds well to reduction of dietary sterols and to ezetimibe or sequestrants [21]. There are no randomised trials with clinical outcomes, and the effects of lowering sitosterol on morbidity and mortality are unknown [13, 23].

7.2. Diet

The first line is restriction of plant sterols, shellfish sterols and cholesterol [1, 13, 20]. Vegetable oils (corn, sesame, soya, rapeseed, peanut, rice bran), margarine, nuts and seeds, avocado, chocolate, soya products and shellfish, which contains brassicasterol of algal origin, should be avoided; and, as regards cholesterol, liver and eggs [1, 13, 18, 66]. Potatoes, carrots and apples contain fewer plant sterols [13]. Plant sterol content ranges from about 7 mg/100 g (potato, tomato) to 686–952 mg/100 g (corn oil) [13]. Products enriched with plant sterols or stanols, recommended to lower cholesterol in the general population and advocated by the EAS consensus for patients at relatively high cardiovascular risk or with statin intolerance, are contraindicated in sitosterolaemia [1, 13, 20].

The efficacy of diet alone is variable. In the five French patients, cholesterol fell markedly with diet alone [45], and in the Beijing series nine of twelve children were treated only with a diet low in xenosterols and cholesterol, with improvement in cholesterol, xanthomas and anaemia [18]. In the Vietnamese series, more than three months of diet alone in ten children lowered total cholesterol from 10.7 to 8.4 mmol/L and LDL-C from 8.2 to 6.1 mmol/L, without statistical significance, and all remained above normal values; adherence was difficult when meals were eaten at nursery or school [49]. A diet low in phytosterols reduced LDL plant sterols by 32%, without a significant effect on LDL-C [49]. In the published series, follow-up by a dietitian was part of initial management [5, 41].

In the infant, breast milk and formulas contain plant sterols and cholesterol, and parenteral nutrition lipid emulsions contain plant sterols [1, 3]. In Japanese infants with xanthomas during breastfeeding, weaning alone lowered LDL-C and caused the xanthomas to regress [9, 13].

7.3. Agents to avoid

Margarines and products with plant stanols (sitostanol, campestanol) are contraindicated. In two patients fed for 7 to 18 weeks with a margarine enriched with sitostanol and campestanol, cholesterol fell (from 180 to 167 and from 153 to 113 mg/dL) and so did sitosterol and campesterol, but plasma sitostanol rose from 1.6 to 10.1 and from 2.8 to 7.9 mg/dL, campestanol rose, and the fall after discontinuation was very slow; in the rat, stanols were deposited in skeletal muscle (threefold) and cardiac muscle (twofold) [24]. These data justify the GeneReviews contraindication and take precedence over the inclusion of sitostanol among the therapeutic options in a table in Inborn Metabolic Diseases [1, 24, 66]. Foods rich in plant sterols should be eaten in moderation, and diets rich in vegetable oils, formerly prescribed to increase polyunsaturated fat, worsen the disease [1, 6]. With ezetimibe, fibrates other than fenofibrate are not recommended, because of the risk of gallstones [22]. High-dose statin in children has been associated with acute hepatitis [49].

7.4. Ezetimibe

Ezetimibe inhibits NPC1L1 at the enterocyte brush border and reduces absorption of cholesterol and plant sterols, acting upstream of the defect [20, 42]. Together with diet, it is the standard treatment in all the sources consulted, alone or combined with a sequestrant [1, 13, 20, 21].

The 10 mg dose is the same in GeneReviews, the labels and the trials; the sources diverge on the minimum age. The US label approves use from 9 years in sitosterolaemia, based on the 8-week trial, which included four patients aged 9 or more years [22]; the Portuguese SmPC makes no posology recommendation between 6 and 17 years [23]; the Brazilian package insert allows use above 6 years without dose adjustment [79]. Use below 9 years, described in the paediatric series with doses of 2.5 to 10 mg, is outside the conditions of the US and Portuguese labels, and below 6 years also outside the Brazilian package insert, and should be decided by a specialist [18, 41, 49, 79]. There is no guideline dose published for sitosterolaemia below 9 years.

Efficacy on plant sterols has been demonstrated in a randomised trial. In the multicentre, double-blind, placebo-controlled trial, 37 patients aged 9 to 72 years with sitosterol above 5 mg/dL on usual therapy (diet, resins, statins, ileal bypass and/or apheresis) were randomised to ezetimibe 10 mg/day (n=30) or placebo (n=7) for 8 weeks: sitosterol fell by 21% and campesterol by 24% with ezetimibe, versus rises of 4% and 3% with placebo (p<0.001), with a progressive fall at each fortnightly visit and a similar effect with or without a concomitant sequestrant [22, 34]. In the 2-year open-label extension, the 21 patients who completed it had falls of 43.9% in sitosterol and 50.8% in campesterol (p<0.001), and of 10.1% in apolipoprotein B, with the maximum effect in the first year, maintained thereafter [80]. In an 11-year-old girl with subcutaneous xanthomas of the elbows, bilateral carotid bruits, a grade II/VI systolic murmur and platelets of 111,000/µL on colestyramine 2 g/day, the addition of ezetimibe 10 mg/day for one year lowered sitosterol and campesterol by about 50%, abolished the carotid bruits and tuberous xanthomas and raised platelets to 268,000/µL [81]. In the Vietnamese series, ezetimibe or colestyramine combined with diet lowered total cholesterol by 54.9% and LDL-C by 67.3% in the eight children treated for more than three months [49], and in the Brazilian screening programme the mean reduction in LDL-C with treatment was 65% [61]. In the Ibero-American series, 11 of the 16 patients, 5 of them children, received ezetimibe, alone or with a statin, with reduction of xanthomas and LDL-C; in a Mexican boy with a clinical diagnosis of homozygous FH at 5 years and xanthomas, the chin and elbow xanthomas regressed with ezetimibe, and the treatment recorded at the time of publication was ezetimibe 20 mg with atorvastatin 10 mg, an ezetimibe dose above the 10 mg/day of the labels [22, 50].

The most frequent adverse effects in monotherapy in the trials (≥2% and above placebo) were upper respiratory tract infection, diarrhoea, arthralgia, sinusitis, pain in extremity, fatigue and influenza [22]; arthralgia has been described as an adverse effect in two patients with sitosterolaemia [49]. The US label recommends measuring transaminases as clinically indicated and considering discontinuation if ALT or AST remain ≥3 times the upper limit of normal (ULN); in combination with a statin, consecutive elevations of this order occurred in 1.3%, versus 0.4% with a statin alone [22]. Myopathy and rhabdomyolysis have been described, mainly in combination with statins or fibrates, as have hypersensitivity reactions (anaphylaxis, angioedema, rash, urticaria), which are the only contraindication in monotherapy [22]. Colestyramine reduces exposure to ezetimibe, hence the interval between doses; ciclosporin increases exposure to both drugs and requires monitoring [22]. Exposure increases about 1.7-fold in mild hepatic impairment and 3- to 6-fold in moderate or severe impairment [22].

7.5. Bile acid sequestrants

Sequestrants (resins) interrupt the enterohepatic circulation of bile acids and increase sterol elimination; the Japanese guideline estimates a reduction in sitosterol of about 30% with resins and about 20% with ezetimibe [13]. GeneReviews proposes them when the response to ezetimibe is incomplete [1]. In one of the first cases, colestyramine reduced cholesterol by 21% and plant sterols by 16% [6]. No sequestrant has an approved indication for sitosterolaemia; use is off-label.

Below 12 years, the sitosterolaemia sources describe only doses from case series. In FH, an analogous condition treated with the same drug, Inborn Metabolic Diseases gives colestyramine 12–24 g/day from 12 years, 4 g up to three times daily from 6 to 11 years and, in homozygous FH below 6 years, 1–2 g up to four times daily, with possible deficiency of vitamins A, D and K during prolonged treatment; application of these doses to sitosterolaemia is an extrapolation [86]. The same source gives ezetimibe 10 mg/day in FH, as the paediatric dose in the table, without a minimum age or maximum dose defined in the source [86].

Colestimide, used in Japan, is cited as an alternative in Japanese reviews, without a dose described in the sources consulted [46].

7.6. Statins

Statins do not lower plant sterols, because HMG-CoA reductase is already suppressed, and the LDL-C response is generally weak; in some patients they lower LDL-C and in others they may increase sitosterol [13, 20, 41]. The cardiogenetics book and the Japanese guideline allow them when LDL-C is raised and, at least, in secondary prevention [5, 13, 20]. In patients treated as FH before the correct diagnosis, simvastatin had a poor response and rosuvastatin 20 mg/day caused acute hepatitis in a child, which resolved one month after discontinuation [49]; in a French patient, the statin was stopped because of a fall in platelets that, with the diagnosis, was attributed to the sitosterolaemia itself [5]. In a Finnish case and a Brazilian case with CAD, rosuvastatin was combined with diet and ezetimibe in secondary prevention [39, 72]. The authors of the Ibero-American series consider statins ineffective as monotherapy and accept them in combination with ezetimibe in patients with established cardiovascular disease; in that series, the Portuguese patient with infarction at 35 years was on ezetimibe with rosuvastatin, and a Spanish patient with aortic stenosis was on atorvastatin 80 mg without ezetimibe [50].

7.7. Severe or refractory disease

For advanced atherosclerosis resistant to treatment, the Japanese guideline mentions LDL apheresis, not reimbursed in Japan [13]; reviews propose apheresis and PCSK9 inhibitors (PCSK9i) in selected severe cases, based on the hypothesis that LDL-C drives atherosclerosis, without trials in sitosterolaemia [5, 46]. The French patient with late diagnosis underwent LDL apheresis until 2018 and then alirocumab 150 mg every two weeks, an off-label use described in a single case [5]. In the Ibero-American series, a Portuguese patient with coronary bypass at 23 years and genetic diagnosis at 50 years was on a PCSK9i with atorvastatin and ezetimibe, also off-label and without description of the individual response; β-sitosterol on that treatment was 39 µmol/L [50]. Partial ileal bypass reduces plasma and cellular sterols and stanols by 50% or more, but since ezetimibe it is reserved as a last resort [1]. Liver transplantation, performed in a patient with cirrhosis, almost completely normalised plant sterols, but it is not a treatment for sitosterolaemia without end-stage liver disease [13, 40].

7.8. Treatment of manifestations

Arthralgia, arthritis, anaemia, thrombocytopenia and splenomegaly are treated first by treating the sitosterolaemia and then with the specialist's usual measures [1]. Ezetimibe and diet increased platelets and reduced haemolysis and spleen size in 2025–2026 series [41, 69–71], but in four transfusion-dependent Indian patients the fall in sterols did not normalise haemoglobin, which suggests irreversible red cell membrane damage in a subgroup [43]. Xanthomas regress within 1–2 years in many treated children [18, 81], and even with persistently raised plant sterols tendon xanthomas can decrease markedly within 5 years with diet and resins [6]. Coronary and valve disease is treated according to cardiology standards [5, 39].

7.9. Regulatory status

In Brazil, active registrations are listed in the open data of the Brazilian Health Regulatory Agency (ANVISA) [87], and the ANVISA-approved Ezetrol® professional package insert includes homozygous familial sitosterolaemia, allows use above 6 years without dose adjustment and does not recommend it below that age [79]. In Portugal, medicines without a marketing authorisation and medicines with a marketing authorisation that are not marketed or are out of stock can be obtained by hospitals through an INFARMED exceptional use authorisation (AUE), requested when the medicine is indispensable and there is no therapeutic alternative, or purchased from distributors or manufacturers that have been granted an AUE [89]; this is the route by which Quantalan® is being distributed [88].

7.10. Clinical trials

The only published randomised trial measured a biochemical outcome over 8 weeks, with seven patients in the placebo arm; there are no trials with clinical outcomes (cardiovascular events, mortality, lesion regression), and the publications do not present confidence intervals for the percentages [13, 34]. The open-label extension lost patients during follow-up and has no control group [80]. The higher-dose trial (40 mg/day) was completed without public results, which makes it impossible to know whether there was additional benefit; absence of publication is not proof of inefficacy [90]. Paediatric and long-term data come from retrospective series, with sterol measurement not always available [18, 49].

7.11. Developments in the last 12 months

Between November 2025 and October 2026 no new drugs, registered trials, marketing applications or label changes specific to sitosterolaemia appeared in the sources consulted [22, 90]. The developments are diagnostic and epidemiological, all from observational studies:

7.12. Pregnancy and lactation

There are no guidelines for pregnancy [1]. The US label considers data on ezetimibe in pregnancy insufficient to assess risk, with no adverse developmental effects in rats and rabbits at exposures up to 10 and 150 times human exposure, and recommends use only if the benefit justifies the fetal risk [22]. The Portuguese SmPC allows ezetimibe in pregnancy only "if clearly necessary" and contraindicates combination with a statin in pregnancy and breastfeeding [23]. Ezetimibe passes into rat milk and there are no human data; the US label advises against use during breastfeeding unless the benefit justifies the risk [22]. Colesevelam is not absorbed and no fetal exposure is expected, but it reduces absorption of fat-soluble vitamins, as does colestyramine, for which prenatal supplementation may not be sufficient [82, 84]. In a 2026 report, a primigravida with thrombocytopenia and an ABCG8 variant started ezetimibe during pregnancy; thrombocytopenia was the only complication, she underwent emergency caesarean section at 37 weeks, and mother and newborn did well [91]. A diet low in plant sterols remains the basis during pregnancy and breastfeeding [1, 13].

7.13. Surgery, anaesthesia and transition

The sources consulted do not describe specific perioperative recommendations. Platelet count and assessment of haemolysis before invasive procedures follow from the presence of macrothrombocytopenia and a bleeding tendency in some patients [4, 41]. At transition to adulthood, the homeostatic shift of puberty lowers cholesterol and alters the response to ezetimibe, which requires treatment and targets to be reassessed [44]; the EAS consensus recommends that children be followed by paediatricians with experience in dyslipidaemias and adults by an experienced lipidologist, endocrinologist, cardiologist, gastroenterologist or family doctor [21].

7.14. Recommendations and divergences between sources

8. Reproductive Options and Family Counselling

8.1. Recurrence risks

Inheritance is autosomal recessive [1, 6, 7]. The parents of a patient are, as a rule, obligate heterozygotes; parental testing is recommended, because de novo occurrence of one of the variants is rare but possible [1]. When two variants are found in a patient, study of the parents confirms that they are in trans [3].

Carriers are usually asymptomatic, but some have slightly raised plant sterols [1]. Heterozygosity in ABCG5 is associated with LDL-C about 25 mg/dL higher and an odds ratio for CAD of 2.06, which justifies assessment of the lipid profile of heterozygous relatives, especially those with another cause of hypercholesterolaemia [10, 54]. In the Vietnamese series, carrier relatives were informed of this risk and advised to undergo surveillance [49]. In a Brazilian case, the heterozygous brother had mild dyslipidaemia [39], and in an Australian case the heterozygous brother of a homozygote had slightly raised sterols [56].

8.2. Cascade testing

Early diagnosis of siblings and other at-risk relatives is made by targeted molecular testing when the familial variants are known, or by plant sterol measurement when they are not [1, 5]. In the Brazilian cascade screening programme, a further 6 patients and 18 carriers were identified from 8 index cases [61]; in the Ibero-American series, 4 of the 16 cases were detected by cascade screening [50]; and in the Vietnamese series, two asymptomatic siblings were diagnosed by family screening [49]. There are no specific guidelines for cascade screening in sitosterolaemia [58]. Carrier testing in relatives requires the familial variants, because measurement does not reliably identify carriers [1]. In the Hutterite and Amish communities, the founder variants allow population carrier screening [1].

8.3. Prenatal and preimplantation diagnosis and counselling of minors

With the familial variants identified, prenatal diagnosis and preimplantation genetic testing are possible [1]. The disease is treatable with diet and an oral drug, and genetic testing is mainly confirmatory [3]. Testing of minor siblings has direct benefit, because early treatment prevents complications and xanthomas may appear in the first year of life [1, 41]. GeneReviews recommends offering genetic counselling to young adults who are affected, carriers or at risk of being carriers, preferably before a pregnancy, and considering DNA banking for probands without a confirmed molecular diagnosis [1].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Frequency

The true frequency is unknown and the estimates measure different things. The number of published cases grew from about 45 in 2003 to 80–100 in 2008, about 110 molecularly confirmed in 2020, 155 in the review of 2002–2024 reports and about 200 according to a 2026 review [1, 5, 12, 13, 60]. The cardiogenetics book refers to about 50 cases worldwide [20], and Orphanet records 100 cases and a point prevalence below 1/1,000,000 [2]. Genetic estimates are much higher: from ExAC loss-of-function variants (excluding missense), at least 1/2.6 million for ABCG5 and 1/360,000 for ABCG8 [3]; from the frequency of about 1/220 individuals with a loss-of-function variant in ABCG5 or ABCG8, about 1/200,000 [13, 46]. In the Dallas Heart Study, among 2542 adults with plant sterols measured, one had sitosterolaemia, which gives a 95% confidence interval of 1/384 to 1/48,076 [1]. These estimates are not national prevalences, and the difference between published cases and genetic estimates reflects underdiagnosis, because routine cholesterol measurement does not measure plant sterols [1, 13].

9.2. Europe and founder populations

In Europeans ABCG8 predominates, with ABCG8 p.(Trp361Ter) as the most frequent loss-of-function variant [3]. The variant was found in the homozygous state in a patient from a Scottish island community, and data from the Viking Genes Project showed more heterozygotes among people with all four grandparents from the Scottish islands than in the UK population [16]; it has also been described in the first Polish family and in a Finnish patient [72, 74]. The Amish and Mennonite ABCG8 variant p.(Gly574Arg) shares a haplotype with a Swiss patient and has a European origin more than 250 years ago [6]. In the Schmiedeleut Hutterites of the USA, ABCG8 p.(Ser107Ter) is private to the community, with 127 heterozygotes and 4 homozygotes among 1515 screened (carrier frequency 0.084, 1/12) [6]; in North America, Hutterite carriers have been estimated at 8% and Old Order Amish carriers at up to 4% [1]. In Kosrae, Micronesia, screening of 932 adults identified three patients (two asymptomatic) and an ABCG8 founder variant with 13.8% carriers [15]. In Qatar, among 5385 unrelated participants in the Qatar Genome Program, carrier frequencies were about 1/215 (ABCG5) and 1/192 (ABCG8), about 1/102 combined, with an estimated disease burden of 1/7509 taking consanguinity into account, versus 1/251 carriers and 1/383,744 patients estimated in gnomAD [17]. In France, a series of five patients referred for suspected homozygous FH and a case diagnosed at 61 years document underdiagnosis [5, 45].

9.3. Asia

In Chinese, Japanese and Indian patients ABCG5 predominates [1, 3]. The ABCG5 variants p.(Arg446Ter), p.(Arg389His) and c.904+1G>A account for more than one third of the alleles in the Japanese catalogue and predominate in East Asia [12]. In the review of 131 Chinese cases, ABCG5 accounted for 77.1% [48]. In Japan, 0.6% of 487 patients with clinical FH had biallelic sitosterolaemia [54]. Recent Indian series show a predominantly haematological presentation, with ABCG8 frequent [43, 69, 70].

9.4. Portugal and Brazil

The Instituto Nacional de Saúde Doutor Ricardo Jorge (INSA) in Lisbon coordinated the Ibero-American series of 16 molecularly confirmed cases (12 index cases and 4 relatives identified by cascade screening): one from Argentina, one from Mexico, four from Portugal, seven from Spain and three from Uruguay; the patients from Argentina, Mexico and Uruguay were sequenced in Portugal [50]. Of the 16, 15 patients had biallelic ABCG8 variants and one had a homozygous ABCG5 frameshift variant; xanthomas were present in 56%, all had first been diagnosed as FH, with delays of up to 30 years, and ezetimibe, alone or with a statin, improved biochemical and clinical parameters [50]. According to the authors, with this series the number of published cases in the Ibero-American region rose to 32 [50]. The same group has recommended since 2018 an eight-gene panel for FH, capable of identifying phenocopies such as sitosterolaemia, which it considers one of the most relevant and underdiagnosed [27].

In Portugal, 3 of the 1291 individuals referred for clinical suspicion of FH had sitosterolaemia, a local detection rate of about 0.23%, which rises to 0.7% when the denominator is restricted to the 420 positive index cases; all patients in the series had markedly raised LDL-C and were first diagnosed with FH, an error the authors associate with inappropriate recommendations, such as plant sterol supplements [50]. The four Portuguese patients belong to three families and have different genotypes: two members of one family are homozygous for ABCG8 p.(Tyr658Ter), one patient is compound heterozygous for ABCG8 p.(Trp361Ter) and p.(Tyr492Ter), and one patient is homozygous for ABCG5 p.(Phe630LeufsTer8) [50]. Three of the variants found in the Brazilian FH screening programme were also identified in the series, all in Portuguese patients, which the authors interpret as a possible founder effect or common ancestry, without haplotype study [50, 61].

Cholesterol values are those at the time of clinical diagnosis, untreated, unless indicated; β-sitosterol was measured at different points in the course [50]. In the patient with bypass at 23 years, the genetic diagnosis came 30 years after the clinical one; in the patient with infarction at 35 years, both diagnoses were made in that year; for the series as a whole, the authors consider that diagnostic delay will have contributed to premature cardiovascular events in two patients [50]. Family 4 was already included in the Portuguese Familial Hypercholesterolaemia Study. Between 1999 and 2017, this study included 731 index cases with a clinical diagnosis of FH according to the Simon Broome criteria (311 children and 420 adults). It found a causal FH variant in 39%, polygenic hypercholesterolaemia in at least 29% and a genetic cause of the phenotype in 69% (503/731) [51]. In a selected subgroup of patients without a variant in the FH genes, sequencing of the phenocopy genes identified a single index case with sitosterolaemia: a child homozygous for ABCG8 c.1974C>G p.(Tyr658Ter). Cascade screening added an adult relative with sitosterolaemia [51]. This index case corresponded to 1 of the 133 paediatric index cases with monogenic dyslipidaemia (about 1%) and to 1 of the 6 index cases with a monogenic cause other than FH (2% of 288). The other five were three children with lysosomal acid lipase deficiency, one child with congenital analbuminaemia and one adult with an APOE variant [51]. Because ABCG5 and ABCG8 were studied only in the selected subgroup, the proportion of 1 in 731 index cases (0.14%) is a minimum value and not a systematic detection rate [51]. The genotype, family composition (index case in childhood and adult relative) and laboratory coincide with those of family 4 of the Ibero-American series (cases 4 and 5, homozygous for p.(Tyr658Ter)). Everything indicates that these are the same patients, although neither publication states this explicitly; the 2025 series cites the 2020 one only in relation to the detection rate [50, 51]. Families 3 and 5 of the 2025 series (cases 3 and 6, both with genetic diagnosis in adulthood) do not appear among the index cases of the 2020 publication, which included no adult with sitosterolaemia [50, 51]. The 3 Portuguese index cases of the 2025 series among 1291 referred individuals correspond to families 3, 4 and 5, and only family 4 overlaps with the 2020 publication [50, 51]. Over the extended period from 1999 to 2021, the Portuguese Familial Hypercholesterolaemia Study received 1005 index cases with a clinical diagnosis of FH according to the Simon Broome criteria, and non-FH monogenic causes, among them sitosterolaemia, lysosomal acid lipase deficiency, congenital analbuminaemia and dysbetalipoproteinaemia, were identified in seven index cases [55]. In Brazil, the FH cascade screening programme of the Instituto do Coração (InCor) in São Paulo found sitosterolaemia in 3.1% of index cases negative for the FH genes, with 14 patients, 78.6% of adults with atherosclerotic disease and 83% with haematological changes [27, 61]; a patient followed for 21 years [52] and a patient from Belo Horizonte with infarction at 27 years [39] have also been published. A Brazilian review recommends testing ABCG5/ABCG8 in patients meeting FH criteria without a variant in the FH genes [92].

9.5. Special populations

In infants, the diagnosis depends on diet (breast milk, formula, parenteral nutrition) [1]. In pregnancy, there are no guidelines [1, 91]. In consanguineous families, other recessive diseases may coexist, such as familial Mediterranean fever or nephronophthisis [13, 48].

9.6. Reference networks and patient resources

There is no ERN dedicated to dyslipidaemias; MetabERN (European Reference Network for Hereditary Metabolic Disorders) has a subnetwork for peroxisomal and lipid-related disorders [25]. The FH Europe Foundation brings together patient organisations for FH and other genetic dyslipidaemias [26]. GeneReviews lists the Sitosterolemia Foundation, the American Heart Association, MedlinePlus and the STAIR (Sterol and Isoprenoid Research) consortium of the Rare Diseases Clinical Research Network [1]; in October 2026 the Sitosterolemia Foundation domain had no active content. Plant sterol measurement is available only in specialist laboratories [3, 21].

10. Illustrative Clinical Case

Leão and colleagues, from the Endocrinology Department and the Medical Genetics Department of the Universidade Federal de Minas Gerais in Belo Horizonte, published in 2025 the case of a Brazilian man in whom the correct diagnosis and targeted treatment became possible only after the molecular diagnosis [39].

A 17-year-old boy was referred in 2005 to the Endocrinology clinic for suspected congenital dyslipidaemia. Since the age of 5 he had had painful tendon xanthomas, first on the Achilles tendons and then on the elbows, wrists and knees, with polyarthralgia and hypercholesterolaemia due to LDL-C. The parents were consanguineous; of the three siblings, one was healthy, another had died shortly after birth and the third had Crohn's disease and ankylosing spondylitis. There was no family history of dyslipidaemia or premature atherosclerosis. Examination showed bilateral yellowish palpebral plaques, scaly lesions on the elbows and knees and thickening of the Achilles and patellar tendons (Figure 2). Total cholesterol was 243 mg/dL, LDL-C 177 mg/dL, HDL cholesterol 50 mg/dL, triglycerides 83 mg/dL and platelets 78 × 10⁹/L. Phytosterol measurement was not available [39].

Because CTX was suspected, he underwent brain magnetic resonance imaging, which showed subtle symmetrical signal changes in the dentate nuclei of the cerebellum, the frontoparietal periventricular white matter, the corticospinal tracts and the globi pallidi. MRI of the knees and Achilles tendons showed chronic tendinopathy suggestive of xanthomas, confirmed by Achilles tendon biopsy. He started chenodeoxycholic acid, which was stopped because of lack of response, diarrhoea, epigastric pain, pruritus and hyperbilirubinaemia. During irregular follow-up he developed persistent thrombocytopenia (down to 46 × 10⁹/L) without a defined cause. In 2015, at 27 years, he had an acute myocardial infarction treated with stent implantation in the left anterior descending artery, and started secondary prevention with rosuvastatin 10 mg, acetylsalicylic acid 100 mg and clopidogrel 75 mg daily [39].

In 2018, after multidisciplinary discussion, sequencing of CYP27A1 was negative and that of ABCG8 identified the nonsense variant p.(Trp361Ter) (NM_022437.3:c.1083G>A, classified as pathogenic or likely pathogenic in ClinVar) in the homozygous state (Figure 3); the healthy brother, with mild dyslipidaemia, was heterozygous (Figure 1) [30, 37, 39]. With a diet restricted in vegetable fats and ezetimibe, there was a good clinical and metabolic response: LDL-C fell to 56 mg/dL in 2023 and platelets rose to 132 × 10⁹/L (Figure 4). Coronary CT angiography in 2021 showed no new plaques or stenoses, and the stent was patent [39].

The case brings together the most common diagnostic errors: CTX was the first hypothesis because of the xanthomas, the absence of family history and the subtle MRI changes, and the thrombocytopenia remained unexplained for more than a decade. The clues to sitosterolaemia were present from adolescence: xanthomas in the first decade with LDL-C of 177 mg/dL, consanguineous parents without dyslipidaemia and thrombocytopenia [5, 13, 39]. Lack of access to plant sterol measurement, common outside specialist centres, left the diagnosis dependent on genetics [3, 39]. The rosuvastatin started after the infarction corresponds to the use in secondary prevention accepted by the Japanese guideline, which does not regard it as treatment of the sitosterolaemia itself [13]. The Australian series of Gamage and colleagues illustrates the haematological phenotype, with macrothrombocytes and stomatocytes on the blood film of a 15-year-old girl (Figure 2 of Gamage 2025), whose haemolysis and thrombocytopenia resolved with diet and ezetimibe 10 mg/day [41].

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis

Prognosis depends on age at diagnosis, diet and treatment. The cases of infarction and sudden death between 5 and 33 years, aortic stenosis and the coronary complications described occurred mainly in undiagnosed or untreated patients [1, 5, 39]. In the catalogue of reports, 14.2% had ischaemic heart disease and 14.2% valve disease, with the publication bias towards severe cases [12]; in the Brazilian FH screening programme, 78.6% of patients, all adults, had clinical or subclinical atherosclerotic disease at diagnosis [61]. By contrast, the 21 Hutterite homozygotes treated with ezetimibe over two decades, identified mainly by screening, were mostly asymptomatic and without stigmata [44], the five treated French patients had no significant subclinical atherosclerosis [45], and the treated children in the paediatric series had regression of xanthomas and correction of anaemia [18, 41]. The Brazilian patient treated for 21 years had no cardiovascular events [52]. These treated-disease data do not allow lifetime risk to be estimated, and the absence of events in small series does not mean zero risk. Haematological changes usually respond to treatment, except in a subgroup with persistent haemolysis [43, 69].

11.2. Surveillance plan

GeneReviews recommends annual surveillance of plant sterols, cholesterol, xanthomas, full blood count with platelets and transaminases, and non-invasive imaging of coronary and carotid plaque and of the valves, especially after long-standing untreated disease [1]. The labels add reassessment of LDL-C from 4 weeks after starting ezetimibe and monitoring of transaminases as clinically indicated [22], and monitoring of triglycerides and of the risk of fat-soluble vitamin deficiency with sequestrants [82, 84].

12. Summary and Concluding Remarks

Sitosterolaemia is an autosomal recessive disease caused by biallelic variants in ABCG8 (STSL1) or ABCG5 (STSL2), the two half-transporters that form the intestinal and hepatic pump responsible for excluding plant and shellfish sterols from the body [6–8]. Loss of this barrier leads to hyperabsorption of all sterols and reduced biliary excretion, with plasma sitosterol and campesterol tens of times above normal, suppression of hepatic cholesterol synthesis and a diet-dependent plasma cholesterol, sometimes in the homozygous FH range in childhood and normal in the adult [1, 6, 44].

The main presentations are tendon and tuberous xanthomas in the child, premature coronary and aortic valve disease, and a haematological picture of haemolytic anaemia with stomatocytes, macrothrombocytopenia and splenomegaly, which may be the only manifestation and is often mistaken for ITP [4, 12, 67]. Misdiagnosis as FH, homozygous or heterozygous, and as CTX is frequent and may last for decades, with unnecessary treatments and missed opportunities for prevention [5, 39, 50].

Diagnosis requires clinical suspicion and two tools little used in routine practice: chromatographic measurement of plant sterols, with sitosterol of 1 mg/dL or more, and sequencing of ABCG5/ABCG8 on a dyslipidaemia panel with CNV analysis [1, 13, 21]. Sitosterol in the intermediate zone, infancy and breastfeeding, parenteral nutrition, cholestasis and prior treatment with ezetimibe or resins limit the biochemistry, and a single variant or none does not exclude the disease when sterols are raised [1, 18, 77]. The European consensus requires sitosterolaemia to be excluded before homozygous FH is diagnosed [28].

Treatment rests on a diet low in plant and shellfish sterols and in cholesterol, without products enriched with sterols or stanols, and ezetimibe 10 mg/day, with sequestrants as adjuncts and statins in secondary prevention [13, 24, 34]. Ezetimibe has an approved indication in the USA from 9 years, in Brazil above 6 years and in Portugal without a paediatric posology recommendation, and its use in young children rests on case series [18, 22, 23]. There are no trials with clinical outcomes, and evidence on long-term benefit comes from small treated cohorts [13, 44]. Cascade testing of siblings and lipid assessment of carriers, especially of ABCG5, complete the family approach [1, 10].

The prevalence estimated from genomic databases is much higher than the number of published cases, and inclusion of ABCG5/ABCG8 in FH panels, as in Portugal and Brazil, and measurement of plant sterols in unexplained macrothrombocytopenia or haemolysis, as in the Turkish screening, increase the number of patients identified [3, 27, 61, 71].

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