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The clinical and molecular diversity of homozygous familial hypercholesterolemia in children: Results from the GeneTics of clinical homozygous hype... - PubMed - NCBI

2018 Dec 19. pii: S1933-2874(18)30476-8. doi: 10.1016/j.jacl.2018.12.003. [Epub ahead of print]

The clinical and molecular diversity of homozygous familial hypercholesterolemia in children: Results from the GeneTics of clinical homozygous hypercholesterolemia (GoTCHA) study.

Luirink IK1, Braamskamp MJAM2, Wiegman A3, Hartgers ML4, Sjouke B4, Defesche JC5, Hovingh GK4.

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Abstract

BACKGROUND:

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.

OBJECTIVE:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSION:

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.