Compound heterozygous low-density lipoprotein receptor variants causing homozygous of familial hypercholesterolemia...

Familial hypercholesterolemia (FH) is a severe hereditary lipid metabolism disorder. Homozygous FH (HoFH) in particular was marked by rapid disease progression, with afflicted children at risk of developing coronary heart disease or even suffering from fatal myocardial infarction in their teenage years. This case report is aim to deepen understanding of HoFH's complexity and provide a scientific foundation for early diagnosis, personalized therapy to improve treatment protocols and reduce the burden on patients and families.

We report two Chinese sisters presenting with multiple xanthomas from early childhood. Laboratory results showed markedly elevated total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels. Genetic testing revealed compound homozygous variants in the low-density lipoprotein receptor (LDLR) gene: a synonymous variant (c.1216C>A, p.Arg406Arg) likely affecting mRNA (messenger RNA) splicing inherited from the mother, and a missense variant (c.1879G>A, p.Ala627Thr) from the father. Both variants were classified as potentially pathogenic based on SpliceAI prediction, clinical phenotype, and co-segregation in the family. Treatment with rosuvastatin and ezetimibe yielded limited LDL-C reduction. In the elder sister, a single dose of evolocumab reduced LDL-C by 27.1% and led to partial regression of xanthomas within 15 days.

This study underscores the critical importance of early diagnosis and treatment in HoFH and highlights the necessity for ongoing research into more effective therapeutic strategies. Through this report, we aim to deepen the understanding of HoFH's complexity and foster the development of improved treatment protocols. Ultimately, our in-depth analysis aspires to provide a scientific foundation for early diagnosis, risk assessment, personalized therapy, and comprehensive management of FH, thereby alleviating the health burden imposed on affected patients and their families.