Xanthomas Can Be Misdiagnosed and Mistreated in Homozygous Familial Hypercholesterolemia Patients: A Call for Increased Awareness Among Dermatologists and Health Care Practitioners

Abstract

Background: Familial hypercholesterolemia (FH) is an autosomal dominant inherited genetic disorder and results in the development of coronary artery disease (CAD). Clinical diagnosis of homozygous HH patients is usually straightforward because persistent hypercholesterolemia can produce xanthoma and corneal arcus. However, xanthoma may also be misdiagnosed as skin lesions and could therefore be mistreated. The aim of this case study report is to highlight the plight of patients with FH as means of raising awareness of the condition among dermatologists and health care practitioners, also to determine the genotype-phenotype correlation in severely affected homozygous FH proband patients. Methods: Genetic screening of FH associated genes was performed by Ion Torrent next-generation sequencing and cascade screening by capillary sequencing. Results: We present two clinical cases with prominent skin lesions seen in a dermatology clinic that were referred to plastic surgery for excision. Genetic testing was performed later, and confirmed common single nucleotide deletion variant (c.2027delG) in the LDLR alleles consequent to a frameshift mutation p.(G676Afs*33). In addition to the LDLR variant, two possibly damaging APOB variants p.(L3313I) and p.(L1212M) and three damaging variants p.(R19*), p.(G83Q) and p.(S474*) in APOC3, PON2 and LPL genes respectively were identified. The PON2 gene variant p.(G83Q) was found to be novel, while others have been previously reported. Both patients were refractory to pharmacological therapies and are currently on lipoprotein apheresis (LA). Conclusions: The present report indicates the need for increased awareness of FH, among the public and healthcare practitioners and supports the need for diagnostic screening and cascade genetic testing of this high-risk condition, which could ultimately lead to better prevention of CHD in this lethal condition.

Case Series of Genetically Confirmed Index Cases of Familial Hypercholesterolemia in Primary Care

“…Clinically, the key characteristics of patients with FH are severely elevated low-density lipoprotein cholesterol (LDL-c), premature corneal arcus (<45 years old), and tendon xanthomas, predominantly in the Achilles tendon and on the extensor tendons of the elbows, hands, knees, and toes [ 7 , 8 ]. FH can be identified and diagnosed using established clinical diagnostic criteria, such as Simon Broome (SB) criteria [ 9 ] and Dutch Lipid Clinic Criteria (DLCC) [ 10 ].…”

“…HoFH is rarely reported [ 12 ], with a global prevalence estimated at 1 in 160 000 to 1 in 300 000 [ 7 ]. HeFH is more common, with a global prevalence estimated at 1 in 200 to 1 in 500 [ 13 ].…”

Importance of the detection of genetic diseases associated with cardiovascular risk in pediatric age

“…Each one is highly suggestive of HF [8,9]. Most pediatric patients do not show clinical manifestations, however, among them, tendon xanthomas are classic findings, their presence orients more towards HoFH instead of HeFH [10]. There are other causes that can lead to HF, such as hypothyroidism, nephrotic syndrome, congenital analbuminemia, obesity or anorexia, obstructive liver disease, among others [11].…”

Familial Hypercholesterolemia in the Arabian Gulf Region: Clinical results of the Gulf FH Registry

“…Various studies have reported that FH is underdiagnosed and undertreated. Among the estimated 34 million individuals with FH, only 1% are identified in most countries [ 10 – 12 ]. Therefore, a reduction in cardiovascular disease (CVD) risk requires early detection and management of FH, particularly in the presence of premature atherosclerotic cardiovascular disease (ASCVD).…”