Epidemiological data showed that the prevalence of FH was 0.28 percent in general population and 7.1 percent in patients with myocardial infarction in China.5, 6 Another study showed a prevalence of 3.5 percent FH in patients undergoing CAG examination, using genetic diagnosis criteria.7 China accounts for more than one fifth of the world's population. There are about 3.8 million potential FH patients in China.8 However, the underdiagnosis and undertreatment was common.
Several diagnostic criteria have been reported to identify FH. Among them, DNLC criteria were the most accepted and commonly used criteria in clinical diagnosis.3 According to scores, patients were defined as definite (>8 scores), probable (6-8 scores), or possible (3-5 scores). In 2018, consensus among Chinese experts on screening, diagnosis and treatment of familial hypercholesterolemia was published.9 FH should be diagnosed clinically in children with LDL-C >3.6 mmol/l before treatment, and the family history of FH or premature CAD in first-relatives.
Undoubtedly, the above criteria are mainly based on clinical phenotypes to diagnose FH. However, genetic diagnosis is the gold standard for diagnosing FH,10 which may reduce the occurrence of misdiagnose. In current case, we firstly reported the homozygous mutation in LDLR exon9 1187-10G>A (IVS8-10G>A), which is a 3' splice acceptor mutation in polypyrimidine tract of intron 8, using DNA Sanger sequencing method in Chinese population. Up to date, 1741 mutations were recorded in LDLR mutation database (http://www.ucl.ac.uk/ldlr/Current/) and most of them were detected only once. LDLR exon9 1187-10G>A mutation was only reported in Canadian,11 Pilipinos,12 and French.13 Mutation of the G-to-A in the -10 position of the splicing acceptor site might create potential aberrant splice sites according to neural-network computed estimation,13 which might lead to abnormal expression of LDLR. This might be partly of reason lipid-lowing drugs having limited effect on the reduction of LDL-C. In addition, this case suffered from serious lesion in cardiac valves and coronary artery in childhood, which might be due to this homozygous mutation.
Statins remain the most common lipid-lowing drugs in FH. However, several prospective studies showed that although most patients were on the maximum lipid-lowering therapy, only 11 % had reached the target of LDL-C levels.14 In this case, although given statin and other lipid-lowing drugs, TC levels still increased from 15.38 mmol/l in 2005 to 20.17 mmol/l in 2010, followed by a mild decrease. This initial elevation of TC levels might be due to the natural process in children. So, we might underestimate lipid levels in children sometimes, which also suggested that monitor lipid changes in FH children is important. Whether or not to screening FH in children is still a controversial topic. If the plasma LDL-C concentration is not controlled efficiently, progressive aortic valve stenosis and calcification and coronary atherosclerosis will occur. We found progressive aortic root stenosis, multiple calcification and thickening in cardiac valves and coronary artery stenosis in this boy.
Early diagnosis and effective treatment are both critical for prevention the cardiovascular events in FH patients. PCSK9 inhibitors, including Evolocumab and Alirocumab, could attractively decrease the LDL-C levels in FH and statins intolerance and have been approved by FDA and CFDA.15 As the human IgG2 monoclonal antibody, PCSK9 inhibitors can block the interaction between PCSK9 and LDLR, decreasing the degradation of LDLR, then increasing the levels of LDLR on the surface of hepatocytes and facilitating the clearance of plasma LDL-C. In recent years, several RCTs and meta-analysis showed that PCSK9 inhibitors reduced LDL-C levels greatly not only in HeFH, but also in HoFH patients.16, 17 The HAUSER-RCT study, which is the largest randomized, placebo-controlled study with PCSK9 inhibitor being conducted in the pediatric patients aged 10 to 17 years with HeFH, is ongoing and expects to obtain the efficacy and safety data in these patients.18 Despite its definitive lipid-lowering effect, the study on the cost-effectiveness of PCSK9 Inhibitor therapy in patients with HeFH revealed that PCSK9 inhibitor use did not meet generally acceptable incremental cost-effectiveness thresholds, according to the prices in 2015, which might hinder the extensive use worldwide,19 especially in developing countries, such as in China. With the increasing attention to FH and wildly use of PCSK9 inhibitors in China, we hope more and more FH patients will get effective therapy.
For HoFH, the early diagnosis and effective treatment was critical to prevent arteriosclerosis and cardiovascular events. HoFH with c.1187-10G>A mutation in LDLR gene might lead to severe damage in cardiovascular system and unsatisfactory response to conventional lipid-lowing drugs. Other aggressive treatments should be used in HoFH patients with this mutation as early as possible.