Table 5.

Genetic Disorders with Feature(s) Similar to Those of Familial Hypercholesterolemia

Gene(s)DiffDx DisorderMOIFeatures of DiffDx Disorder
Similar to FHDistinguishing from FH
ABCG5
ABCG8 		Sitosterolemia ARXanthomas; susceptibility to early-onset CAD. Some persons may present w/↑ plasma cholesterol/LDL-C (often presents in childhood).Hematologic abnormalities (hemolytic anemia, thrombocytopenia, stomatocytes); xanthomas in childhood (particularly in absence of hyperlipidemia in parents); poor response to statins
APOE p.Leu167del-related AD hypercholesterolemia 1ADPersons may present w/↑ LDL & ↑ risk of CAD.Splenomegaly, sea-blue histiocytosis, thrombocytopenia, & ↑ triglycerides reported in some p.Leu167del heterozygotes
Hyperlipoproteinemia type III (familial dysbetalipoproteinemia [FD]) (OMIM 617347)AR
AD 2		Persons w/predisposing APOE variants are at risk of developing xanthomas (more commonly cutaneous & tuberous) & premature CAD. Most common APOE genotype assoc w/FD: homozygosity for E2 allele (p.Arg176Cys); however, >30 APOE variants have been assoc w/FD. 2Persons w/FD are at risk of developing ↑ triglycerides.
CYP27A1 Cerebrotendinous xanthomatosis (CTX) ARXanthomasDementia, ataxia, & cataracts; normal LDL-C
LIPA Lysosomal acid lipase deficiency AR↑ LDL-C; risk of CAD
  • In infantile onset (Wolman disease): ↑ triglycerides, malnutrition, hepatosplenomegaly, liver disease, adrenal cortical insufficiency
  • In adult onset (cholesterol-ester storage disease): hepatosplenomegaly &/or ↑ liver enzymes, ↑ triglycerides

AD = autosomal dominant; AR = autosomal recessive; CAD = coronary artery disease; DiffDx = differential diagnosis; FH = familial hypercholesterolemia; LDL = low-density lipoprotein; LDL-C = low-density lipoprotein cholesterol; MOI = mode of inheritance

1.
2.

From: Familial Hypercholesterolemia

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