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

  • 13 Patients carried two deleterious variants in the LDLR gene. Untreated LDL-c levels were between 5.62 to 20.8 mmol/L. 8 Patients (62%) had LDL-c levels <13 mmol/L. Almost half (n=6, 46%) had xanthoma’s.
  • One HoFH patient had stable angina and coronary atheroma at angiography, but nobody had suffered from a CV event.

Clinical and genetic characteristics in children classified as hEFH

  • 64 Children were classified as heFH, based on identification of a variant in LDLR, in the course of a genetic cascade screening program. They had LDL-c ≥8.36 mmol/L. This means that over 3% of heFH patients had a “hoFH”-like phenotype.
  • In 43 children with extreme LDL-c levels, NGS was performed. None met the clinical EAS/ESC hoFH criteria. Four children had clinical FH stigmata at diagnosis (2x xanthoma, 1x arcus lipoides, 1x xanthelasmata). None suffered from CVD at diagnosis. LDL-c ranged from 8.38 mmol/L to 10.86 mmol/L.
  • 29 Genes with an established or a putative effect on lipids and lipoproteins were sequenced in the NGS analysis of 43 heFH patients. The variants identified by PCR in the cascade screening program were confirmed, but no additional pathogenic variants in LDLR or APOB were identified. Two related patients had a gain-of-function mutation in the PCSK9 gene.
  • A variant in the lipoprotein lipase (LPL) gene was found in 3 patients, but these patients showed triglyceride levels in the normal range. Two patients had a pathogenic variant of ABCA1, which may affect HDL-c levels. Indeed one patient showed a low level. One patient had a variant in ABCG5 and two variants in the ABCG8 gene, which may lead to a recessive lipid disorder.


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.


1. Soutar AK, Naoumova RP. Mechanisms of disease: genetic causes of familial hypercholesterolemia. Nat Clin Pract Cardiovasc Med. 2007;4(1743–4300):214–225.

2. Nordestgaard BG, Chapman MJ, Humphries SE, et al. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease. Eur Heart J. 2013;34(45):3478–3490.

3. Sjouke B, Kees Hovingh G, Kastelein JJP, Stefanutti C. Homozygous autosomal dominant hypercholesterolaemia: prevalence, diagnosis, and current and future treatment perspectives. Curr Opin Lipidol. 2015;26(3):200–209.

4. Cuchel M, Bruckert E, Ginsberg HN, et al. Homozygous familial hypercholesterolaemia: new insights and guidance for clinicians to improve detection and clinical management. A position paper from the Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society. Eur Heart J. 2014;35(32):2146–2157.

5. Bertolini S, Pisciotta L, Rabacchi C, et al. Spectrum of mutations and phenotypic expression in patients with autosomal dominant hypercholesterolemia identified in Italy. Atherosclerosis. 2013;


6. Sánchez-Hern andez RM, Civeira F, Stef M, et al. Homozygous familial hypercholesterolemia in Spain: prevalence and phenotypegenotype relationship. Circ Cardiovasc Genet. 2016;9:504–510.

7. Mabuchi H, Nohara A, Noguchi T, et al. Genotypic and phenotypic features in homozygous familial hypercholesterolemia caused by proprotein convertase subtilisin/kexin type 9 (PCSK9) gain-of-function mutation. Atherosclerosis. 2014;236(1):54–61.

Find the article online at Science Direct

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