Abstract
Homozygous familial hypercholesterolemia (HoFH) and compound heterozygous familial hypercholesterolemia (cHeFH) are rare disorders generated by disease-causing variants in both alleles of the LDLR or other familial hypercholesterolemia (FH)-related genes. HoFH and cHeFH are characterized by severely elevated low-density lipoprotein-cholesterol (LDL-C), frequently leading to early cardiovascular disease. We investigated the genetic and clinical characteristics of HoFH and cHeFH patients from the Slovenian FH registry and/or those who were previously diagnosed or managed at our institution (Slovenian, Pakhtun and Albanian ethnicity), where genetic testing is not available. Our study includes seven patients. Their median age at the time of clinical diagnosis was 6.3 years (2.9–12.9 years); 2/7 were females. Two patients were diagnosed through the universal FH screening and five patients were diagnosed due to the presence of xanthomas. All the mutations are present in LDLR gene: 7 different genotypes for HoFH (p.Cys167Leu, p.Asp178Asn, p.Cys243Tyr, p.Gly549Asp, p.Cys27Trp, p.Ile585Thr and p.Val797Met) and p.Gly549Asp/p.Gln384Pro genotype for cHeFH patient. The median initial level of LDL-C was 17.0 mmol/L [655 mg/dL] (range 7.6–21.6 mmol/L). The HoFH/cHeFH patients are clinically and genetically very diverse. The clinical criteria (as Simon Broome criteria) might be applicable already in children to raise suspicion of FH but in some cases fail to distinguish heterozygous FH and HoFH/cHeFH patients. However, genetic testing is helpful in confirming the diagnosis, also for a prompt awareness, better compliance to treatment and family screening.
Highlights
Familial Hypercholesterolemia (FH) is an autosomal dominant genetic disorder, characterized by elevated total cholesterol (TC) and LDL-cholesterol (LDL-C) levels, usually accompanied by clinical characteristics and an early onset of cardiovascular disease (CVD), with a variable severity depending on the causative mutation (Moorjani et al, 1993)
Homozygous familial hypercholesterolemia (FH) can be classified as: a- Real homozygous (HoFH): when the same mutation affects both alleles of one of the major FH-related genes (LDLR, APOB, or PCSK9); b- Compound heterozygous: when different mutations located on different alleles affect one of the major FH-associated genes; cCombined heterozygous: when different mutations affect two different FH-related genes (Masana et al, 2019)
The universal hypercholesterolemia screening in children is an obligatory part of the blood check-up at the programed visit in 5-year old children at the primary care pediatricians; if TC is elevated, the child is referred to the tertiary center for the FH genetic screening (Groselj et al, 2018)
Summary
Familial Hypercholesterolemia (FH) is an autosomal dominant genetic disorder, characterized by elevated total cholesterol (TC) and LDL-cholesterol (LDL-C) levels, usually accompanied by clinical characteristics and an early onset of cardiovascular disease (CVD), with a variable severity depending on the causative mutation (Moorjani et al, 1993). Homozygous FH patients can develop xanthomas and progressive atherosclerosis already in early childhood. If untreated, they develop vascular lesions and CVD before the second decade of life and die before the end of the third decade (Watts et al, 2014; Vallejo-Vaz et al, 2015). Slovenia has successfully implemented nationwide universal screening for FH in pre-school children, detecting the HoFH/cHeFH patients (Klancar et al, 2015; Groselj et al, 2018). The implementation and optimization of the routine FH genetic testing enables us to offer it to other national and foreign centers
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