Heterozygous familial hypercholesterolemia: an underrecognized cause of early cardiovascular disease

Abstract

Heterozygous familial hypercholesterolemia (HeFH) is a monogenic disorder that affects about 1 in 500 people, with a higher prevalence in certain subpopulations such as people of Quebecois, Christian Lebanese and Dutch South Afrikaner extraction. HeFH is characterized by cholesterol deposits affecting the corneas, eyelids and extensor tendons; elevated plasma concentrations of low-density lipoprotein (LDL) cholesterol; and accelerated vascular disease, especially coronary artery disease (CAD). Although HeFH is genetically heterogeneous, it is most often caused by heterozygous mutations in the LDLR gene encoding the LDL receptor. We describe a man who was diagnosed with HeFH after he had a myocardial infarction at 33 years of age. By DNA sequence analysis, he was found to have a heterozygous splicing mutation in his LDLR gene. This discovery expanded the growing mutational spectrum in patients with HeFH in Ontario. Given that HeFH is a treatable cause of early vascular disease, it is important that this condition be recognized, diagnosed and treated in affected patients; but as yet, there is no consensus on the best approach. Diagnostic criteria based on family history and clinical presentation have been proposed for patients with suspected HeFH. Biochemical or molecular screening might be considered to detect new cases of HeFH in populations with a relatively high HeFH prevalence and a relatively small number of possible causative mutations. So far, however, the most cost-effective and efficient systematic strategy to detect previously undiagnosed cases of HeFH is still cascade testing: clinical and biochemical screening of close relatives of the proband patient diagnosed with HeFH. Pharmacologic treatment of HeFH is cost-effective.

Fig. 1: Physical signs of heterozygous familial hypercholesterolemia (HeFH), which result from cholesterol deposited within macrophages in specific sites. Tendinous xanthomas, for example, manifest first as thickening of, and later as deposits within, extensor tendons. A: Lateral borders of thickened Achilles' tendons are shown with arrows. B: Tendinous xanthomas can also occur in the extensor tendons of the hands (shown), feet, elbows and knees. C: Xanthelasmas are cholesterol deposits in the eyelids. D: Arcus cornealis results from cholesterol infiltration around the corneal rim (arrow). Deposits in and around the eye tend to be more specific for HeFH in people younger than 45 years; in elderly people, they are less likely to be associated with blood lipoprotein abnormalities, for instance in the case of arcus senilis. Some patients may report having observed cutaneous cholesterol deposition in response to a functional enquiry. People with HeFH have been known to undergo cosmetic eyelid surgery to remove xanthelasmas — even repeatedly, for lesions that continued to recur — without ever having had their plasma lipoprotein profiles determined.

Box 1

Box 2