Familial Hypercholesterolemia: A Narrative Review on Diagnosis and Management Strategies for Children and Adolescents

Abstract

Familial hypercholesterolemia (FH) is a relatively common inherited disorder caused by deleterious mutation(s) in the low-density lipoprotein (LDL) receptor or its associated genes. Given its nature as a heritable disease, any useful screening scheme, including universal, and cascade screening, allows for the early identification of patients with FH. Another important aspect to note is that early diagnosis associated with appropriate treatment can promote better prognosis. However, most clinical diagnostic criteria for adults have adopted clinical elements, such as physical xanthomas and family history, both of which are usually obscure and/or difficult to obtain in children and adolescents. Moreover, LDL cholesterol levels fluctuating considerably during adolescence, hindering the timely diagnosis of FH. In addition, recent advancements in human genetics have revealed several types of FH, including conventional monogenic FH, polygenic FH caused by common single nucleotide variations (SNV) accumulation associated with elevated LDL cholesterol, and oligogenic FH with multiple deleterious genetic variations leading to substantially elevated LDL cholesterol. The aforementioned findings collectively suggest the need for amassing information related to genetics and imaging, in addition to classical clinical elements, for the accurate diagnosis of FH in this era of personalized medicine. The current narrative review summarizes the current status of the clinical and genetic diagnosis of FH in children and adolescents, as well as provide useful management strategies for FH in children and adolescents based on currently available clinical evidence.

Keywords: adolescents; cardiovascular disease; children; familial hypercholesterolemia; statin.

Figure 1

Strategies for the management of pediatric familial hypercholesterolemia (FH) (JAS). Green arrows indicate “Yes”; blue arrows indicate “No.” The essential message is that the pediatric patients with FH aged 10 or greater who have low-density lipoprotein cholesterol levels ≥180 mg/dL under appropriate lifestyle intervention may be treated using statins. Reproduced from Harada-Shiba M, Ohta T, Ohtake A, et al. Joint Working Group by Japan Pediatric Society and Japan Atherosclerosis Society for Making Guidance of Pediatric Familial Hypercholesterolemia. Guidance for Pediatric Familial Hypercholesterolemia 2017. J Atheroscler Thromb. 2018;25(6):539–553.

Figure 2

Strategies for the diagnosis and management of familial hypercholesterolemia (FH) in children and adolescents (EAS). Premature coronary heart disease is defined as a coronary event before age 55 and 60 years in men and women, respectively. Definite FH is defined as genetic confirmation of at least one FH-causing genetic mutation. Close relative is defined as 1st or 2nd degree relatives. Highly probable FH is based on clinical presentation (ie, phenotypic FH): either an elevated low-density lipoprotein cholesterol (LDL-C) level ≥5 mmol/L in a child after dietary intervention or a LDL-C level ≥4 mmol/L in a child with a family history of premature coronary heart disease in close relatives and/or high baseline cholesterol in one parent. Cascade screening from an index case with a FH-causing mutation may identify a child with elevated LDL-C levels ≥3.5 mmol/L. Reproduced with permission from Wiegman A, Gidding SS, Watts GF, et al. European atherosclerosis society consensus panel. Familial hypercholesterolaemia in children and adolescents: gaining decades of life by optimizing detection and treatment. Eur Heart J. 2015;36(36):2425–2437.