Severe hypercholesterolemia in a pediatric cohort: Familial homozygous and autosomal recessive hypercholesterolemia

Familial hypercholesterolemia (FH) is a genetic disorder characterized by impaired clearance of low-density lipoprotein cholesterol (LDL-C), leading to severe hypercholesterolemia and increased risk of premature cardiovascular disease (CVD). Our study aims to describe and compare the clinical, biochemical, and genetic profiles of pediatric patients diagnosed with FH based on LDL-C levels exceeding 400 mg/dL (10.4 mmol/L) and confirmed by biallelic pathogenic variants in low-density lipoprotein receptor (LDLR) or low-density lipoprotein receptor adapter protein-1 (LDLRAP1) genes.

This retrospective cohort study included 39 pediatric patients diagnosed with FH at a tertiary care center. Clinical data were analyzed, including age at diagnosis, family history, lipid profile, presence of xanthomas, and cardiovascular complications. Molecular analysis was conducted using next-generation sequencing (NGS) and Sanger sequencing to confirm pathogenic variants. Statistical comparisons were performed between the LDLR and LDLRAP1 variant groups regarding lipid profiles, treatment response, and cardiovascular outcomes.

Among 39 patients, 32 and 7 had pathogenic variants in LDLR and LDLRAP1 genes, respectively. Genetic analysis identified 27 unique pathogenic variants in LDLR (including 5 novel mutations) and 4 in LDLRAP1 causal for autosomal recessive hypercholesterolemia (ARH), highlighting the molecular diversity of FH. Compared to the LDLR variant group, LDLRAP1 variant patients had significantly lower untreated LDL-C levels (640.0 ± 155.6 mg/dL [16.6 ± 4.0 mmol/L] vs 506.9 ± 130.1 mg/dL [13.1 ± 3.4 mmol/L], P = .026] and showed a superior response to lipid-lowering therapy (LLT), with a greater percentage (70.6% ± 12.0%) reduction in LDL-C levels (P = .015). While xanthomas were present in 62.5% of LDLR variant patients, they were less frequent (42.9%) in the LDLRAP1 group (P = .107). Cardiovascular complications were observed exclusively in LDLR variant patients. Fourteen patients required lipoprotein apheresis (LA), and one underwent liver transplantation due to severe aortic stenosis.

This study highlights the importance of genetic testing in differentiating classical semidominant homozygous FH from ARH, given their phenotypic overlap but distinct treatment responses. LDLRAP1 variant patients with ARH exhibit better LDL-C reductions with conventional LLT, suggesting a milder phenotype. Early diagnosis, aggressive LLT, and novel treatments are essential to mitigate cardiovascular risk. Future studies with larger cohorts and long-term follow-ups are needed to refine treatment strategies for pediatric FH.