Background

Familial hypercholesterolemia (FH) is a common genetic condition that affects 1 in ~300 persons worldwide. The lifetime risk of coronary artery disease is estimated to be 10-fold increased in affected patients. However, FH is underdiagnosed and undertreated. The diagnosis of FH is traditionally based on clinical scores such as the Dutch Lipid Clinic Network (DLCN) criteria. Those include, among others, the presence of cutaneous manifestations of FH, i.e. xanthomata and arcus cornealis. These scores have been established several decades ago in highly selected patients and may not apply to the full spectrum of a current day European population.

Objective

The objective of this study was to systematically evaluate cutaneous manifestation in a contemporary cohort of patients clinically diagnosed with FH.

Methods and Results

A total of 223 patients of a single center lipid clinic at a German University Hospital with the clinical diagnosis of FH were included. The mean age was 52.5 years, 58% were female. 22.9% of patients had a diagnosis of coronary artery disease, 5.4% had a history of stroke or transient ischemic attack, and 7.2% had peripheral artery disease. The highest untreated LDL-C was 6.9 (SD 2.1) mmol/L (Table).

Among all patients, 14.3% had cutaneous manifestations. An arcus cornealis before the age of 45 was present in 0.9%, xanthomata in 1.8%, and xanthelasmata – which are not part of the DLCN criteria – in 12.1%. Of all cutaneous manifestations, xanthelasmata represented 84.4% (Figure).

In 42.6% (n=95) of the patients, genetic analysis was available. In these patients, 50.5% (n=48) had genetic variants known to cause FH. Of the carriers of FH mutations, 8.3% (n=4) had an arcus cornealis or xanthomata (i.e., the cutaneous manifestations included in the DLCN score) and xanthelasmata were present in n=12 patients (25.0%). Among the patients without genetic finding causal for FH, no patient had an arcus cornealis or xanthomata, and 8.5% had xanthelasmata.

Conclusions

The most common cutaneous manifestations in a contemporary cohort of patients with clinical diagnosis of FH are xanthelasmata. Cutaneous manifestations used in scores such as the DLCN criteria (i.e., arcus cornealis and xanthomata) were only present in a minority of patients (2.2%) but more frequent in carriers of established FH mutations (8.3%). The traditional focus on cutaneous manifestations may need to be revised in order to reduce the high number of non-diagnosed individuals with FH.



Table: Baseline characteristics