PM1046: Characterization of Children with Homozygous Familial Hypercholesterolemia from the CASCADE FH Registry

Background: Homozygous familial hypercholesterolemia (HoFH) is a rare inherited condition associated with extremely elevated levels of serum low-density lipoprotein cholesterol (LDL-C) and risk of premature atherosclerotic cardiovascular disease (ASCVD) as early as the first decade of life. Clinical diagnosis is made based on LDL-C levels and the presence of positive family history and/or xanthomas. The American Academy of Pediatrics (AAP) recommends lipid screening for children with a family history of ASCVD or FH at age 2 and universal screening between ages 9-11.

Methods: The current analysis includes a total of 67 HoFH patients enrolled at sites participating in the CASCADE-FH® registry, a multi-site patient registry created in 2013 by the Family Heart Foundation that tracks the characteristics, treatment patterns and clinical events in heterozygous [HeFH] and HoFH patients in the US. Here a comparison is made between 16 HoFH patients who were children ( < 18 years old) and 51 who were adults at time of enrollment.

Results: Age of diagnosis (median; IQR) was 2.0 years (2.0/3.5) in children and 12.6 years (4.1/26.5) in adults. Untreated levels of LDL-C (median; IQR) in the children were extremely elevated at 776 mg/dL (704/892) and significantly higher than untreated levels in the HoFH adults at 533 mg/dL (467/702) (p=0.001). At enrollment, 18.8% and 43.8% of the children had evidence of aortic valve stenosis (AS) and ASCVD, respectively, median age of onset for ASCVD was 8.9 years. The earliest reported ASCVD diagnosis occurred at ages 2 and 3 years in children who underwent liver transplant at 4 and 8 years respectively. Two children underwent coronary artery bypass grafting at ages 6 and 14. Five subjects underwent liver transplant prior to age 18. Despite a more severe phenotype, children had not uniformly developed tendon xanthomas or corneal arcus and had younger family members with lower rates of ASCVD (Table 1). Treatment reduced LDL-C substantially, but only 42% of children achieved LDL-C goal.

Conclusion: HoFH patients enrolled in the CASCADE-FH registry as children were diagnosed earlier and had higher untreated LDL-C than their adult counterparts, raising the possibility that only children with the most severe phenotypes are diagnosed before adulthood. Neither family history of ASCVD, nor physical findings (xanthomas or corneal arcus) reliably identified children. Moreover, at enrollment over half the children had evidence of ASCVD or AS. These findings and recent improvement in lipid lowering therapies make a compelling case for rigorous compliance with AAP’s guidelines for screening at age 2 in children with a family history of FH or ASCVD. This should be followed by cascade family screening. Unfortunately, even routine screening between ages 9-11 is rare in the US. A country-wide call for consistent screening is warranted. Only then, will all children with HoFH be consistently identified.