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

• Main Authors: Al-Khateeb, A.M (Author), Chua, Y.-A (Author), Mohd Kasim, N.A (Author), Mohd Nawawi, H. (Author), Mohd Nor, N.S (Author)
• Format: Article
• Language: English
• Published: BioMed Central Ltd. 2019
• Subjects: ABC transporter G5; ABC transporter G8; ABCG5 gene; ABCG8; ABCG8 gene; ABCG8 protein, human; adult; Adult; APOB100 gene; APOE gene; apolipoprotein B100; apolipoprotein E; Article; ATP Binding Cassette Transporter, Subfamily G, Member 8; blood; case report; child; Child; clinical article; clinical feature; Coronary artery disease; disease severity; Diseases in Twins; DNA; dna mutational analysis; DNA Mutational Analysis; DNA sequence; exon; Familial hypercholesterolaemia; familial hypercholesterolemia; female; Female; genetic screening; Genetic Testing; genetic variability; genetics; heterozygote; human; Humans; Hyperlipoproteinemia Type II; intron; LDLR; LDLR gene; LDLR protein, human; LDLRAP1 gene; lipid analysis; low density lipoprotein receptor; male; Male; metabolism; middle aged; Middle Aged; missense mutation; monozygotic twins; Mutation, Missense; mutator gene; next generation sequencing; PCSK9 gene; pedigree; Pedigree; phenotype; Phenotype; Premature atherosclerosis; procedures; proprotein convertase 9; Receptors, LDL; school child; twin study; twins; Twins, Monozygotic
• Online Access: View Fulltext in Publisher; View in Scopus

 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. © 2019 The Author(s).