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Digenic Overlap Syndrome Masquerading as Homozygous Familial Hypercholesterolemia

Samuel D Maidman1, Chen Gurevitz1, Robert S Rosenson1

  • 1Metabolism and Lipids Program, Icahn School of Medicine at Mount Sinai, Mount Sinai Fuster Heart Hospital, New York, New York, USA.

JACC. Case Reports
|July 11, 2025
PubMed

Insights

Familial hypercholesterolemia (FH) can mimic sitosterolemia, a rare genetic disorder. This case highlights the importance of genetic testing for severe hypercholesterolemia to ensure accurate diagnosis and personalized treatment.

Area of Science:

  • Biochemistry
  • Genetics
  • Metabolic Disorders

Background:

  • Familial hypercholesterolemia (FH) is characterized by high LDL cholesterol and childhood xanthomas.
  • Homozygous FH typically presents with LDL cholesterol >400 mg/dL.
  • Tendinous xanthomas in childhood suggest homozygous FH.

Observation:

  • A patient presented with severe hypercholesterolemia and childhood xanthomas, meeting criteria for homozygous FH.
  • Genetic and absorption testing revealed a digenic overlap of heterozygous FH and heterozygous sitosterolemia.
  • The patient exhibited marked elevations in cholesterol absorption indices.

Findings:

  • Sitosterolemia, a disorder of plant sterol hyperabsorption, can cause xanthomatosis and mimic FH.
  • Heterozygous sitosterolemia can present with intermediate phenotypes.
  • Ezetimibe treatment led to a significant reduction in LDL cholesterol.

Implications:

  • Accurate diagnosis of severe hypercholesterolemia requires comprehensive genetic and biochemical profiling.
  • Personalized therapy is crucial for managing complex lipid disorders.
  • Recognizing sitosterolemia as a differential diagnosis for FH is important.
Abstract

Keywords:
ABCG8LDLRfamilial hypercholesterolemiasitosterolemiaxanthomas

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