Ipercolesterolemia Familiare in età pediatrica: come migliorare diagnosi e gestione dei pazienti. Familial hypercholesterolemia in pediatric age: how to improve diagnosis and management

Heterozygous familial hypercholesterolemia (HeFH) is one of the most common genetic disorders, but it remains significantly underdiagnosed, limiting opportunities for timely and effective intervention. Individuals with HeFH exhibit persistently elevated low-density lipoprotein cholesterol (LDL-C) levels from birth, which are associated with an increased risk of atherosclerotic cardiovascular disease. Since the atherosclerotic process begins in childhood, early diagnosis is essential to enable prompt treatment. Statins represent the cornerstone of therapy, alongside lifestyle and dietary recommendations, and new therapeutic options are emerging. This thesis project comprises three studies on HeFH. The first study retrospectively evaluated eight diagnostic criteria and scoring systems for HeFH in relation to genetic findings in the main FH-associated genes (LDLR, APOB, PCSK9) in a pediatric cohort of 214 subjects with suspected HeFH, defined by LDL-C ≥95th percentile for age and sex in both the proband and one biological parent. Pathogenic variants were identified in 92.3% of subjects. Diagnostic approaches using lower LDL-C thresholds minimized the number of variant-positive individuals missed (notably the Japanese Atherosclerosis Society criteria and FH-PeDS, with a missed diagnosis rate of 1.6%), whereas more restrictive criteria excluded a substantial proportion of affected patients, particularly the Dutch Lipid Clinic Network score and Simon Broome Register criteria (56.3% and 10.5% missed diagnoses, respectively). The mutation detection rate exceeded 91% for all evaluated criteria and scores. The second study investigated the role of polygenic risk scores (PRS), based on 12 and 6 single nucleotide polymorphisms (SNPs), in patients with suspected HeFH. This analysis was motivated by evidence that a proportion of patients with a clinical FH phenotype lack detectable mutations in known genes, suggesting a polygenic etiology. A total of 55 pediatric patients in the monocentric study and 424 subjects (290 adults and 134 pediatric patients) in the multicentric study were enrolled. PRS distributions largely overlapped between mutation-positive (V+) and mutation-negative (V−) individuals; however, higher scores were observed in V− subjects. Using a cut-off that classified 80% of V−/USV− individuals as score-positive, a higher prevalence of score positivity was observed in V− than in V+ for both the 12-SNP and 6-SNP scores (p = 0.010 and 0.033, respectively). Among V+ patients, higher LDL-C levels were associated with positive PRS status, particularly for the 12-SNP score (p = 0.006). Multivariate analysis confirmed the association between PRS and LDL-C levels, with a stronger effect observed in children. The third study assessed adherence to the Mediterranean diet (MD) and its impact on lipid profiles in 157 pediatric patients with primary dyslipidemia (including both HeFH and polygenic hypercholesterolemia). Adherence was evaluated using the KIDMED score at baseline and after a six-month nutritional intervention. KIDMED scores improved in 65% of patients. Improvements in KIDMED scores (even a one-point increase) were significantly associated with reductions in LDL-C, non-HDL-C, and total cholesterol levels (p < 0.0001). In conclusion, we demonstrated that several currently used diagnostic criteria may underestimate the number of children carrying FH-associated variants, whereas less restrictive approaches enable the identification of a greater proportion of affected individuals without compromising mutation detection rates. Furthermore, polygenic risk scores may account for hypercholesterolemia in patients without detectable pathogenic variants and contribute to LDL-C variability among mutation carriers. Finally, adherence to the Mediterranean diet, as assessed by the KIDMED score, was associated with significant improvements in lipid profiles in children with both monogenic and polygenic dyslipidemia.