Sitosterolaemia

Sitosterolaemia presents with markedly variable expressivity, ranging from severe childhood-onset disease to a clinically silent biochemical phenotype. Tendon and tuberous xanthomas are characteristic and have been reported in children as young as one to two years, often in atypical locations such as the buttocks, heels, elbows and knees. Premature atherosclerosis, occasionally complicated by sudden cardiac death, has been described from age 5 to mid-thirties and may manifest as early coronary or carotid disease and valvular involvement. Haematological involvement (haemolytic anaemia, macrothrombocytopenia, and stomatocytosis) may be the presenting or sole feature, with reported haemoglobin values of 76 to 109 g/l and platelet counts as low as 12 to 82 × 10⁹/l. Splenomegaly, abnormal liver transaminases, arthralgias and arthritis have additionally been documented. Intrafamilial variability has been observed in consanguineous families carrying identical genotypes, indicating a substantial influence of modifying factors on the clinical course.

The estimated prevalence is 1/1,000,000 to 1/5,000,000.

Sitosterolaemia results from biallelic germline pathogenic variants in ABCG5 (~42%) or ABCG8 (~58%), both located at chromosome 2p21. The two genes encode the two subunits, sterolin-1 and sterolin-2, of the ABC efflux transporter, which form an obligate heterodimer expressed in intestinal enterocytes and hepatocytes and efflux plant sterols and cholesterol back into the intestinal lumen and the bile. Loss of this heterodimeric pump leads to markedly increased intestinal absorption and decreased biliary excretion of sitosterol, campesterol, stigmasterol and cholesterol.

Sitosterolaemia is inherited in an autosomal recessive manner. At conception, the offspring of two heterozygous carriers carry a 25% risk of being affected, a 50% risk of being heterozygous carriers themselves and a 25% risk of being unaffected non-carriers. Prenatal molecular testing is technically possible once the familial pathogenic variants have been identified.

The diagnosis is supported by markedly increased plasma plant-sterol concentrations, particularly sitosterol, campesterol and stigmasterol, measured by gas chromatography, GC/MS, HPLC or LC-MS/MS. A plasma sitosterol concentration above 1 mg/dl is considered diagnostic outside the neonatal period; untreated individuals typically show a 30 to 100-fold increase (10 to 65 mg/dl). No formal consensus diagnostic criteria have been established.

Main differential diagnoses include:

• : xanthomas with extreme hypercholesterolaemia, no macrothrombocytopenia and unresponsive to plant-sterol restriction; APOB, LDLR, PCSK9
• Cerebrotendinous xanthomatosis: childhood xanthomas with raised plasma cholestanol, protracted diarrhoea, juvenile cataracts and adult neurological involvement; CYP27A1
• : stomatocytosis with very low HDL-cholesterol on standard lipid profile; ABCA1

• Establishing the molecular diagnosis confirms the clinical suspicion and clarifies the precise genetic aetiology.
• Identifying the underlying pathogenic variants enables specific and individualised surveillance and clinical management; the molecular diagnosis is a prerequisite for targeted medical care, which lies with the treating physicians in consultation with the affected individual.
• Testing of at-risk family members allows early identification of biallelic and heterozygous individuals before symptomatic disease.

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