Familial hypercholesterolemia (FH) arises from variants in genes critical to the receptor-mediated removal of low-density lipoprotein (LDL) particles, which contain LDL cholesterol (LDL-C). This dysfunction hampers the body's ability to clear LDL-C from the bloodstream, resulting in elevated levels that heighten the risk of premature cardiovascular disease (CVD). Consequently, early diagnosis and timely initiation of treatment are crucial (1).

FH manifests in two clinical forms: heterozygous FH (HeFH) and homozygous FH (HoFH). HoFH is linked to biallelic variants in the autosomal semi-dominant genes LDLR, APOB, and PCSK9. LDLRAP1 was also has identified as another causative gene. This gene codes for the low-density lipoprotein receptor adapter protein-1 (LDLRAP1) and the associated hypercholesterolemia phenoptye is inherited in an autosomal recessive manner, clinically referred to as autosomal recessive hypercholesterolemia (ARH) (OMIM #603813) (2,3). Although HoFH classically refers to individuals with biallelic pathogenic variants, in clinical practice the term is also used to describe patients with persistently elevated LDL-C levels (>400 mg/dL), including compound heterozygous FH and ARH. This phenotype-based approach aims to guide timely and aggressive therapy regardless of the specific genotype (4). While LDLR gene variants are most commonly detected in FH patients, LDLRAP1 gene variants are extremely rare, with an estimated occurrence of less than 1 in 1,000,000 individuals (5). Scientific organisations, including the European Atherosclerosis Society (EAS) Consensus Panel, Simon Broome Register (SBR) Group, and Dutch Lipid Clinic Network (DLCN), have established well-known diagnostic criteria based on scores assigned to family history and laboratory parameters (2,6, 7, 8, 9, 10, 11).

In numerous cases of genetically confirmed HoFH, plasma LDL-C levels exceed 400 mg/dL (10.4 mmol/L) (12,13). Most ARH cases are clinically indistinguishable from HoFH; consequently, autosomal recessive FH has been regarded as a phenocopy of HoFH (14). Therefore, it is essential to initiate treatment in HoFH for patients with LDL-C levels above 400 mg/dL (10.4 mmol/L) without awaiting the results of molecular studies. An additional justification for commencing therapy in these patients with markedly elevated LDL-C levels from birth is their substantially increased risk of unexpected and life-threatening early-onset atherosclerotic CVD (7,15).

The conventional lipid-lowering therapy (LLT) modality is high-dose statins combined with ezetimibe. However, given the limited efficacy of these agents in these patients, additional treatments such as PCSK9 inhibitors (evolocumab, alirocumab, evinacumab) or lipoprotein apheresis (LA) are often required, if available (16). Proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors are not approved in our country. Liver transplantation has also been reported to restore LDLR function in several cases (17), but is invasive and requires lifelong immunotherapy. Novel therapies, including small interfering RNA-based therapies and gene editing techniques, are currently under clinical trials and may offer promising future treatment avenues (18).

This study provides a comprehensive overview of the clinical and genetic characteristics of 39 pediatric patients diagnosed with FH with biallelic pathogenic variants in the LDLR and LDRAP1 genes. Our study aims to enhance our understanding of phenotypic similarity and underlying genotypic factors linked to FH in the pediatric population.