Physicians' Academy for Cardiovascular Education

Homozygous FH in children is clinically more diverse than clinical diagnostic criteria suggest

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

Literature - Luirink IK, Braamskamp MJAM, Wiegman A et al., - J Clin Lipidol. 2019; 13(2): 272-278

Introduction and methods

Homozygous familial hypercholesterolemia (hoFH) can be the result of homozygosity, compound heterozygosity, and double heterozygosity for deleterious variants in the genes coding for key proteins involved in the LDL-c metabolism. Many pathogenic variants have been described in the genes encoding the LDL-receptor (LDLR gene), apolipoprotein B (APOB gene), PCSK9 (PCSK9 gene) and LDL-receptor adaptor protein 1 (LDLRAP1 gene) [1]. Recent studies estimate that the prevalence of hoFH may range from approximately 1 in 160.000 to 1 in 300.000 [2,3].

Diagnosis of hoFH is based on identification of molecular defects in the genes mentioned above, or based on phenotypic criteria. A recent EAS/ESC consensus document defined hoFH as either a plasma LDL-c level >13 mmol/L (500 mg/dL) without lipid-lowering treatment (LLT), or LDL-c levels >8 mmol/L (300 mg/dL) on LLT, combined with either the presence of one of more xanthomas before the age of 10 or untreated elevated LDL-c levels consistent with heterozygous FH (heFH) in both parents [4].

Recent studies have demonstrated that such extreme LDL-c levels are often not seen in patients with genetically defined hoFH [4-6]. Also, LDL-c levels in heFH and hoFH have been shown to overlap, thus the clinical criteria may not be truly discriminating [7].

The clinical diversity among children with hoFH has not been addressed, but LDL-c levels are typically lower in children with hoFH. Consequently, a proportion of children with hoFH may be misclassified as having heFH. To increase the understanding of the molecular and phenotypical spectrum in children with heFH and hoFH, a study was conducted in a large cohort of children with FH. It aimed to describe the clinical phenotype of 13 children with molecularly defined hoFH, identify what proportion of patients now classified as heFH had LDL-c levels above the levels observed in the molecularly defined hoFH children, and to perform next generation sequencing (NGS) of the 3 FH genes in the latter category, to address whether additional pathogenic variants are present.

Data of 1903 children aged 0 to 19 years were included, who all had molecular-proven FH (carrier of at least one variant in the LDLR, APOB or PCSK9 genes). Double heterozygous carriers, who have pathogenic variants in two different genes and carriers of the relatively mild FH-Hauwert variant were excluded.

Main results

Clinical characteristics of hoFH

Clinical and genetic characteristics in children classified as hEFH


This analysis of pediatric patients with genetically defined FH revealed that LDL-c levels vary greatly among patients with genetically defined hoFH. About half of these patients would not be classified as

hoFH based on current clinical diagnostic criteria. 3% Of heFH patients have similar or even higher LDL-c levels than patients with genetically defined hoFH. Patients with genetically determined heFH but with a hoFH-like phenotype did not carry a second deleterious variant in LDLR or APOB.

Thus, these data suggest that hoFH in children is more heterogeneous than current clinical criteria suggest. This likely leads to misdiagnosis and possibly undertreatment. Given the overlap between the phenotypes of severe heFH and hoFH, the authors suggest to reconsider the validity of separating the two entities.


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Find the article online at Science Direct

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