The clinical and molecular diversity of homozygous familial hypercholesterolemia in children: Results from the GeneTics of clinical homozygous hypercholesterolemia (GoTCHA) study
Luirink, I.K.; Braamskamp, M.J.A.M.; Wiegman, A.; Hartgers, M.L.; Sjouke, B.; Defesche, J.C.; Hovingh, G.K.
Journal of Clinical Lipidology 13(2): 272-278
Homozygous familial hypercholesterolemia (hoFH) is either diagnosed on the identification of pathogenic genetic variants in LDLR, APOB, or PCSK9 or by phenotypic parameters of which an extremely elevated LDL-C level >13 mmol/L (>500 mg/dL) is the most prominent hallmark. Little is known about the clinical spectrum in children with hoFH. We set out to investigate the phenotypical spectrum of genetically defined hoFH in our pediatric cohort and evaluated how many pediatric patients, now classified as heterozygous, carry a second mutation, which would reclassify these patients as hoFH. We analyzed the data of a total of 1903 children with molecularly proven FH. Subsequently we performed candidate gene sequencing in the cohort of heterozygous familial hypercholesterolemia children in whom the LDL-C level was above the lowest level measured in the pediatric patients with hoFH. Of our 13 hoFH children, 8 (62%) had LDL-C levels below the clinical hoFH criteria of 13 mmol/L (500 mg/dL). In the remaining 1890 patients with heterozygous familial hypercholesterolemia, 64 (3.4%) had LDL-C levels equal to or above the lowest LDL-C level in a patient with hoFH carrying 2 deleterious variants (8.36 mmol/L or 323.3 mg/dL). No additional pathogenic variants in LDLR and APOB were identified. In 2 related patients, a PCSK9 gain of function mutation was found. We show that LDL-C levels vary among pediatric patients with molecularly proven hoFH, and that most of these patients do not meet the clinical LDL-C criteria for hoFH. The levels overlap with LDL-C levels in true heterozygous patients. This warrants a critical reappraisal of the current LDL-C cutoffs for the phenotypic diagnosis of hoFH in children.