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Background and Aims: We aimed to describe the limitations of familiar hypercholesterolemia (FH) diagnosis in childhood based on the presence of the typical features of FH, such as physical sings of cholesterol accumulation and personal or family history of premature cardiovascular disease or hypercholesterolemia, comparing their prevalence in the adult and paediatric FH population, and to illustrate how additional information can lead to a more effective diagnosis of FH at a younger age., Methods: From the Italian LIPIGEN cohort, we selected 1188 (≥18 years) and 708 (<18 years) genetically-confirmed heterozygous FH, with no missing personal FH features. The prevalence of personal and familial FH features was compared between the two groups. For a sub-group of the paediatric cohort (N = 374), data about premature coronary heart disease (CHD) in second-degree family members were also included in the evaluation., Results: The lower prevalence of typical FH features in children/adolescents vs adults was confirmed: the prevalence of tendon xanthoma was 2.1% vs 13.1%, and arcus cornealis was present in 1.6% vs 11.2% of the cohorts, respectively. No children presented clinical history of premature CHD or cerebral/peripheral vascular disease compared to 8.8% and 5.6% of adults, respectively. The prevalence of premature CHD in first-degree relatives was significantly higher in adults compared to children/adolescents (38.9% vs 19.7%). In the sub-cohort analysis, a premature CHD event in parents was reported in 63 out of 374 subjects (16.8%), but the percentage increased to 54.0% extending the evaluation also to second-degree relatives., Conclusions: In children, the typical FH features are clearly less informative than in adults. A more thorough data collection, adding information about second-degree relatives, could improve the diagnosis of FH at younger age., Competing Interests: Declaration of competing interest All authors declare no support from any organization for the submitted work; no other relationships or activities that could appear to have influenced the submitted work. MG, MC, MEC, EO, FG, and CP report no conflict of interest disclosures. ALC received research funding and/or honoraria for advisory boards, consultancy or speaker bureau from Aegerion, Amgen, AstraZeneca, Eli Lilly, Genzyme, Mediolanum, Merck or MSD, Pfizer, Recordati, Rottapharm, Sanofi-Regeneron, Sigma-Tau., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Aims: Little is known about the role of Lp(a) in the assessment of cardiovascular risk in the paediatric population. Trying to clarify the clinical relevance of Lp(a) in risk stratification, the aim of the study is to evaluate the association between Lp(a) plasma levels in children with familial hypercholesterolaemia (FH) and positive family history for premature cardiovascular disease (pCVD) in first- and second-degree relatives., Methods: 653 Caucasian children and adolescents (334 females and 319 males), aged 2-17 years, with diagnosis of FH from a paediatric cohort included in the LIPIGEN Network, were selected. We compared family history of pCVD, lipid and genetic profile in two groups based on Lp(a) levels below or above 30 mg/dL. To determine the independent predictors of pCVD, a multivariate logistic regression was used, with all clinical characteristics and blood measurements as predictors., Results: Subjects with Lp(a) > 30 mg/dl more frequently reported positive family history of pCVD compared to subjects with Lp(a)≤30 mg/dl (69.90% vs 36.66%, p < 0.0001), while did not show differences in terms of median [interquartile range] LDL-cholesterol level (153.00 [88.00 vs 164.50 [90.25] mg/dL, p = 0.3105). In the regression analysis, Lp(a) > 30 mg/dl was an independent predictor of family history of pCVD. Comparing subjects with or without family history of pCVD, we reported significant differences for Lp(a) > 30 mg/dl (46.25% vs 17.65%, p < 0.0001), FH genetic mutation (50.48% vs 40.75%, p = 0,0157), as well as for LDL-cholesterol (p = 0.0013) and total cholesterol (p = 0.0101)., Conclusions: Children/adolescents with FH and Lp(a) > 30 mg/dl where more likely to have a positive family history of pCVD. Lp(a) screening in children and adolescents with FH may enhance risk assessment and help identify those subjects, children and relatives, at increased pCVD risk., (Copyright © 2022. Published by Elsevier B.V.)

Objective: Familial hypobetalipoproteinemia (FHBL) is autosomal codominant disorder of lipoprotein metabolism characterized by low plasma levels of total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-C) and apolipoprotein B (apoB) below the 5(th) percentile of the distribution in the population. Patients with the clinical diagnosis of homozygous FHBL (Ho-FHBL) are extremely rare and few patients have been characterized at the molecular level. Here we report the medical history and the molecular characterization of one paediatric patient with clinical features of Ho-FHBL., Methods: A one month old infant with failure to thrive, severe hypocholesterolemia and acanthocytosis was clinically and genetically characterized. Molecular characterization of the proband and her parents was performed by direct sequencing of the APOB gene and functional role of the identified mutations was assessed by the minigene methodology., Results: The proband was found carrying two novel splicing mutations of the APOB gene (c.3696+1G > C and c.3697-1G > A). CHOK1H8 cells expressing minigenes harbouring the mutations showed that these two mutations were associated with the retention of intron 23 and skipping of exon 24, resulting in two truncated apoB fragments of approximate size of 26-28 % of ApoB-100 and the total absence of apoB., Conclusion: We describe the first case of Ho-FHBL due to two splicing mutations affecting both the donor and the acceptor splice sites of the same intron of the APOB gene occurring in the same patient. The clinical management of the proband is discussed and a review of the clinical and genetic features of the published Ho-FHBL cases is reported., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)