Heterozygous familial hypercholesterolaemia in a pair of identical twins: a case report and updated review

Abstract

Background Familial hypercholesterolaemia (FH) is the most common inherited metabolic disease with an autosomal dominant mode of inheritance. It is characterised by raised serum levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-c), leading to premature coronary artery disease. Children with FH are subjected to early and enhanced atherosclerosis, leading to greater risk of coronary events, including premature coronary artery disease. To the best of our knowledge, this is the first report of a pair of monochorionic diamniotic identical twins with a diagnosis of heterozygous FH, resulting from mutations in both LDLR and ABCG8 genes. Case presentation This is a rare case of a pair of 8-year-old monochorionic diamniotic identical twin, who on family cascade screening were diagnosed as definite FH, according to the Dutch Lipid Clinic Criteria (DLCC) with a score of 10. There were no lipid stigmata noted. Baseline lipid profiles revealed severe hypercholesterolaemia, (TC = 10.5 mmol/L, 10.6 mmol/L; LDL-c = 8.8 mmol/L, 8.6 mmol/L respectively). Their father is the index case who initially presented with premature CAD, and subsequently diagnosed as FH. Family cascade screening identified clinical FH in other family members including their paternal grandfather who also had premature CAD, and another elder brother, aged 10 years. Genetic analysis by targeted next-generation sequencing using MiSeq platform (Illumina) was performed to detect mutations in LDLR, APOB100, PCSK9, ABCG5, ABCG8, APOE and LDLRAP1 genes. Results revealed that the twin, their elder brother, father and grandfather are heterozygous for a missense mutation (c.530C > T) in LDLR that was previously reported as a pathogenic mutation. In addition, the twin has heterozygous ABCG8 gene mutation (c.55G > C). Their eldest brother aged 12 years and their mother both had normal lipid profiles with absence of LDLR gene mutation. Conclusion A rare case of Asian monochorionic diamniotic identical twin, with clinically diagnosed and molecularly confirmed heterozygous FH, due to LDLR and ABCG8 gene mutations have been reported. Childhood FH may not present with the classical physical manifestations including the pathognomonic lipid stigmata as in adults. Therefore, childhood FH can be diagnosed early using a combination of clinical criteria and molecular analyses.

Acute coronary syndrome in an 8-year-old child with familial hypercholesterolemia: a case report

“…Similar to the treatment of patients with HeFH, the current treatment options for HoFH include lifestyle interventions, such as dietary therapy, exercise therapy, smoking cessation and anti-obesity measures [ 14 ]. As atherosclerosis progresses more quickly in patients with HeFH than in their heterozygote counterparts, before providing guidance in exercise therapy and the patient initiating this exercise regimen, the patient should be carefully evaluated for CAD as well as valvular disease and aortic aneurysm [ 1 ].…”

Genes Potentially Associated with Familial Hypercholesterolemia

“…Variants of ABCG5/8 are associated with sitosterolemia and higher levels of total cholesterol and triglycerides as well as lower levels of HDL-C [87] Mutation-negative patients with FH Sanger sequencing [92] Case report of FH Targeted NGS [107] Case/control study of patients with FH TaqMan genotyping [91,93,108] Case/control study of patients with FH Meta-analysis [108] PNPLA5 Individuals with extremely high and extremely low LDL-C from population-based cohorts Whole-exome sequencing Variants of PNPLA5 are associated with extremely high LDL-C levels [104] In 2019, Luis Masana and co-workers proposed a new classification of FH on behalf of the Expert Group of the Spanish Arteriosclerosis Society ( Table 2). The factors that prompted the creation of the new classification were 1) discrepancies between the clinical and genetic diagnosis of FH, when FH-associated mutations are not found in people with the clinical diagnosis of definite FH; 2) variation in the clinical signs of FH; 3) high risk of vascular complications among patients with monogenic or polygenic FH; and 4) treatment of FH confirmed by molecular genetic methods with new classes of drugs [111].…”

“…Clinical classification of patients with FH according to the Expert Group of the Spanish Arteriosclerosis Society, 2019[107].…”

Modeling of hydraulic shock as one of the main risk factors of main arteries atherosclerosis in arrhythmias

“…Причины и механизмы развития атеросклероза изучены достаточно хорошо [1][2][3][4][5]. Однако до сих пор в числе общепризнанных факторов риска отсут ствует указание на возможный старт атерогенеза и прогрессирование его вследствие механического воздействия внутрисосудистых гемодинамических факторов (гидравлического удара) на внутреннюю стенку артерий при нарушениях ритма [6][7][8]. Впервые о возможности влияния волны гидравлического удара первого постэкстрасистолического сокращения и пульсовой волны после длительной паузы между желудочковыми сокращениями при фибрилляции предсердий мы упоминали ранее в наших работах [9][10][11][12][13][14].…”