Heterozygous familial hypercholesterolemia in Italian children: a road map through a single center's experience.

UNLABELLED: This study aims to evaluate the clinical, biochemical, and molecular characteristics of pediatric patients with suspected familial hypercholesterolemia (FH, OMIM #143890) and to investigate whether the presence of pathogenic low-density lipoprotein receptor (LDLR) variants is associated with differences in lipid profile severity and treatment initiation compared with inconclusive genetic findings. We report the clinical, biochemical and molecular data of 382 patients diagnosed in a single pediatric center. Patients carrying pathogenic low-density lipoprotein receptor (LDLR) variants exhibited significantly more severe dyslipidemia compared with those with inconclusive genetic findings, particularly in terms of elevated LDL-C, the hallmark of FH. No significant differences were observed in age, weight, height, or body mass index, confirming that lipid abnormalities are primarily attributable to genetic factors. Treatment uptake was higher in the pathogenic group, with 87% initiating statin-based therapy compared with 50% in the inconclusive group, suggesting that a confirmed genetic diagnosis may improve treatment adherence.

CONCLUSION

Pathogenic variants in the LDLR gene are associated with a more severe lipid profile and a higher likelihood of initiating lipid-lowering therapy. These findings support the clinical value of genetic testing in familial hypercholesterolemia, both for improving diagnostic accuracy and for promoting earlier therapeutic intervention and adherence.

WHAT IS KNOWN: • Familial hypercholesterolemia is a common, treatable genetic disorder, and early diagnosis with lipid-lowering therapy from childhood reduces lifelong cardiovascular risk. • Most cases of heterozygous FH are caused by pathogenic LDLR variants, but data on treatment uptake in children are limited.

WHAT IS NEW: • In 382 Italian children, those with pathogenic LDLR variants had higher LDL-C than those with inconclusive genetic results. Their lipid profiles also differed depending on the exon and protein domain affected. • Treatment was started in 87% of children with a confirmed genetic diagnosis and in 50% of those with inconclusive results. This suggests that genetic confirmation may help families accept treatment.