Keywords: Sitosterolemia; ABCG8; Pediatric dyslipidemia; Familial hypercholesterolemia mimic; Plant sterols; β-sitosterol; Ezetimibe
Case Presentation
A 13-year-old male was referred for
evaluation of persistent hypercholesterolemia despite treatment with
atorvastatin (10–30 mg/day) over approximately two years. The patient was
asymptomatic, with no known personal history of cardiovascular disease. Family
history of premature cardiovascular disease or severe hypercholesterolemia was
not reported. Physical examination did not reveal xanthomas. Baseline lipid
profile prior to referral showed LDL-cholesterol (LDL-C) of 313.4 mg/dL. Given
the working diagnosis of FH, dietary counseling emphasized plant-based fats and
fiber (including frequent use of olive oil, avocado and nuts). Four months
later, the lipid profile showed a paradoxical deterioration, with LDL-C rising
to 412.8 mg/dL; triglycerides were 88 mg/dL. Liver enzymes and thyroid function
tests were within normal limits. The poor response to highdose statin therapy
and the worsening after increasing plant-based fat intake prompted evaluation
for sitosterolemia. Targeted next-generation sequencing identified two ABCG8
variants in heterozygosity: a truncating pathogenic variant c.1974C>G
(p.Tyr658*) and a missense variant of uncertain significance (VUS),
c.1570G>C (p.Gly524Arg). Phase was not established at the time of writing;
parental segregation testing was recommended1,3. Plasma β-sitosterol was
markedly elevated at 35 mg/dL (reference range 1.7–3 mg/dL), supporting the
diagnosis. Atorvastatin was discontinued and ezetimibe 10 mg/day was initiated,
together with dietary restriction of phytosterol-rich foods. On follow-up, the
patient demonstrated substantial improvement of the lipid profile with clinical
improvement: total cholesterol 124.5 mg/dL, LDL-C 59.9 mg/dL and triglycerides
92.4 mg/dL5.
Discussion
Sitosterolemia is considered
rare, yet it is likely underdiagnosed, particularly among children labeled as
FH based solely on lipid levels. Clinical manifestations are heterogeneous and
may include xanthomas, premature atherosclerosis and hematologic findings such
as hemolytic anemia or macrothrombocytopenia; however, some patients present
only with hypercholesterolemia1-3.
In this case, two features were especially informative: (1) minimal benefit
from prolonged statin therapy and (2) deterioration after increasing dietary
plant-based fats, which can be phytosterol-rich. These clues motivated
confirmatory testing with plasma sterol measurement and genetic analysis. In
pediatric cohorts, plasma cholesterol and LDL-C can be markedly elevated and
cardiovascular involvement-including carotid changes-has been reported,
supporting the importance of early recognition and treatment3,6. Molecular confirmation is central. The
ABCG8 truncating variant identified (p.Tyr658*) is consistent with loss of
transporter function. The second variant was reported as a VUS; segregation
studies can help clarify whether the variants are in trans and strengthen
diagnostic certainty. Regardless, the markedly elevated β-sitosterol level and
the clinical/biochemical response to ezetimibe support the diagnosis1,6. Ezetimibe is the preferred
pharmacologic therapy because it inhibits intestinal sterol absorption via
NPC1L1, lowering both cholesterol and plant sterols. In a randomized
placebo-controlled study in sitosterolemia, ezetimibe produced significant
reductions in plasma sitosterol and campesterol concentrations5. Dietary management remains essential,
focusing on reducing phytosterol intake (notably from vegetable oils, nuts,
seeds, avocado and fortified foods), while maintaining overall nutritional
adequacy. Early diagnosis and targeted treatment can normalize lipid levels and
may reduce the risk of early atherosclerosis1,3.
Conclusion
Sitosterolemia should be considered in
children with severe hypercholesterolemia who show limited statin response and
paradoxical worsening after plant-fat-rich dietary interventions. Measuring
plasma plant sterols and confirming ABCG5/ABCG8 variants enable accurate
diagnosis. Timely initiation of ezetimibe and a phytosterol-restricted diet can
lead to rapid and substantial biochemical improvement.
Declarations
Ethics approval and consent to participate
Written informed consent for participation
and publication was obtained from the patient’s legal guardians. Institutional
review board approval was not required for a single anonymized case report, in
accordance with local policies.
Consent for publication
Consent for publication of anonymized
clinical information was obtained from the patient’s legal guardians.
Availability of data and materials
Not applicable. No datasets were generated or
analyzed beyond the clinical record.
Conflicts of interest
The authors declare no conflicts of interest.
Funding
This case report received no external
funding.
Authors' contributions
AS and VL contributed to
clinical evaluation and manuscript drafting. NS supervised the clinical workup
and critically revised the manuscript. DR and MV contributed to literature
review and manuscript editing. All authors read and approved the final manuscript.
Acknowledgements
We thank the patient and his
family for their participation and consent.
References