Background.
Familial dysbetalipoproteinemia (also known as type 3
hyperlipoproteinemia) is typically associated with homozygosity for the
apolipoprotein E2 isoform, but also sometimes with dominant rare missense variants in the
APOE gene. Patients present with roughly equimolar elevations of
cholesterol and
triglyceride (TG) due to pathologic accumulation of remnant
lipoprotein particles. Clinical features include tuberoeruptive
xanthomas, palmar
xanthomas, and premature
vascular disease. Case. A 48-year-old male presented with severe combined
dyslipidemia: total
cholesterol and TG were 11.5 and 21.4 mmol/L, respectively. He had
dyslipidemia since his early 20s, with tuberous
xanthomas on his elbows and knees. His body mass index was 42 kg/m2. He also had treated
hypertension, mild renal impairment, and a history of
gout. He had no history of
cardiovascular disease,
peripheral arterial disease, or
pancreatitis. Multiple medications had been advised including
rosuvastatin,
ezetimibe,
fenofibrate, and
alirocumab, but his
lipid levels were never adequately controlled. Genetic Analysis. Targeted next-generation sequencing identified (1) the
APOE E2/E2 homozygous genotype classically described with
familial dysbetalipoproteinemia; (2) in addition, one
APOE E2 allele contained the rare heterozygous missense variant p.G145D, previously termed
apo E-Bethesda; (3) a rare heterozygous
APOC2 nonsense variant p.Q92X; and (4) a high
polygenic risk score for TG levels (16 out of 28 TG-raising alleles) at the 82nd percentile for age and sex. Conclusion. The multiple genetic "hits" on top of the classical
APOE E2/E2 genotype likely explain the more severe
dyslipidemia and refractory clinical phenotype.