Familial Hypercholesterolemia Cases Research Articles

Addressing comprehensive complexities a striking familial hypercholesterolemia case study.

Premature aortic involvement and comprehensive management strategies in familial hypercholesterolemia familial hypercholesterolemia (FH), a rare autosomal dominant genetic disorder, poses significant challenges due to its propensity for elevated low-density lipoprotein cholesterol, premature coronary heart disease, and vascular atherosclerosis. Unraveling Cardiovascular Complexities: A Striking Familial Hypercholesterolemia. This case study delves into a remarkable instance of FH in a 16-year-old female who presented with chest pain and worsening dyspnea. Diagnostic evaluation revealed distinct electrocardiographic changes, elevated troponin levels, and profound dyslipidemia. Remarkable findings on transthoracic echocardiography, computed tomography angiography, and catheterization prompted multidisciplinary interventions and demonstrated remarkable enhancements in ventricular function, mitral regurgitation, and aortic stenosis. The case study underscores the urgency of comprehensive management strategies in confronting the myriad challenges of FH, emphasizing the value of early intervention, innovative therapies, and rigorous imaging modalities for unraveling the intricate cardiovascular manifestations of this condition.

Recapitulating familial hypercholesterolemia in a mouse model by knock-in patient-specific LDLR mutation.

Familial hypercholesterolemia (FH) is one of the most prevalent monogenetic disorders leading to cardiovascular disease (CVD) worldwide. Mutations in Ldlr, encoding a membrane-spanning protein, account for the majority of FH cases. No effective and safe clinical treatments are available for FH. Adenine base editor (ABE)-mediated molecular therapy is a promising therapeutic strategy to treat genetic diseases caused by point mutations, with evidence of successful treatment in mouse disease models. However, due to the differences in the genomes between mice and humans, ABE with specific sgRNA, a key gene correction component, cannot be directly used to treat FH patients. Thus, we generated a knock-in mouse model harboring the partial patient-specific fragment and including the Ldlr W490X mutation. LdlrW490X/W490X mice recapitulated cholesterol metabolic disorder and clinical manifestations of atherosclerosis associated with FH patients, including high plasma low-density lipoprotein cholesterol levels and lipid deposition in aortic vessels. Additionally, we showed that the mutant Ldlr gene could be repaired using ABE with the cellular model. Taken together, these results pave the way for ABE-mediated molecular therapy for FH.

Like daughter, like mother: two cases of familial hypercholesterolaemia incidentally diagnosed during investigation of premature pubarche and obesity in a 6-year old girl

Like daughter, like mother: two cases of familial hypercholesterolaemia incidentally diagnosed during investigation of premature pubarche and obesity in a 6-year old girl

Prevalent Variants in the LDLR Gene Impair Responsiveness to Rosuvastatin among Family Members of Patients with Premature Myocardial Infarction.

Familial hypercholesterolemia (FH) is an inherited metabolic disorder characterized by high levels of low-density lipoprotein cholesterol (LDL-c) from birth. About 85% of all FH cases are caused by pathogenic variants in the LDLR gene. Individuals with FH have increased cardiovascular risk, including a high risk of premature myocardial infarction (PMI). We conducted an opportunistic exome screening to identify variants in the LDLR gene among Vietnamese patients with PMI treated at a general hospital in southern Vietnam. A cascade testing for LDLR variants was conducted in their relatives within three generations, and the effects of the LDLR variant on the response to rosuvastatin treatment were also studied using a comparative before-and-after study design on those who were eligible. A total of 99 participants from the three generations of four PMI patients were recruited, mean age 37.3 ± 18.5 years, 56.6% males. Sanger sequencing revealed two variants in the LDLR gene: variant rs577934998 (c.664T>C), detected in 17 individuals within one family, and variant rs12710260 (c.1060+10G>C), found in 32 individuals (49.5%) in the other three families tested. Individuals harboring the variant c.664T>C had significantly higher baseline LDL-c and total cholesterol levels compared to those with variant c.1060+10G>C (classified as benign) or those without LDLR variants, and among the 47 patients subjected to a 3-month course of rosuvastatin therapy, those with variant c.664T>C had a significantly higher risk of not achieving the LDL-c target after the course of treatment compared to the c.1060+10G>C carriers. These findings provide evidence supporting the existence of pathogenic LDLR variants in Vietnamese patients with PMI and their relatives and may indicate the need for personalizing lipid-lowering therapies. Further studies are needed to delineate the extent and severity of the problem.

Genetic association between vitamin D receptor gene and Saudi patients confirmed with Familial Hypercholesterolemia.

Familial Hypercholesterolemia (FH) is a common condition caused by inherited genetic abnormalities. Inadequate clearance of the circulating low-density lipoproteins (LDL) is the primary cause of the excessive concentrations of LDL seen in FH patients. The relation with vitamin D deficiency and vitamin D receptor (VDR) gene is well documented in the Saudi Arabia. The aim of this study was to investigate the role of molecular analysis studied between FH patients and fours polymorphisms associated with VDR gene in Saudi Population. In this case-control study, 120 patients were selected, and 50 patients were confirmed as FH and 70 subjects were confirmed as healthy controls. Genotyping was performed with polymerase chain reaction followed by restriction fragment length polymorphism analysis using ApaI, BsmI, TaqI and FokI polymorphisms in the VDR gene. The current study results confirmed no association between clinical characteristics studied between FH cases and controls (p>0.05). Hardy Weinberg Equilibrium analysis was present in ApaI and FokI polymorphisms (p<0.05). Only ApaI (C vs A: OR-15.1 (95% CI:5.78-39.41); p<0.001; AC+CC vs AA: OR-6.59 (95% CI:2.42-17.95); p=0.0006) and BsmI (G vs A: OR-2.88 (95% CI:1.54-5.38); p=0.0006 and AG+GG vs AA: OR-3.79 (95% CI:1.72-8.35); p=0.0007) polymorphisms showed both allele and genotype association between FH patients and controls. ANOVA analysis confirmed that TG levels were associated (p=0.02) with combination of heterozygous and homozygous genotypes present in all four polymorphisms studied in this population. ApaI and BsmI polymorphisms in the VDR gene showed association with FH patients in the Saudi Population.

Prevalence and factors associated with possible cases of familial hypercholesterolemia in Brazilian adults: a cross-sectional study

This study aimed to estimate the prevalence of possible cases of FH and analyze associated factors in the adult Brazilian population. Cross-sectional study with laboratory data from the Brazilian National Health Survey, with 8521 participants. Possible cases of FH were defined according to the Dutch Lipid Clinic Network criteria. The prevalence and 95% confidence intervals (95% CI) of possible cases of FH were estimated according to sociodemographic variables, lifestyle, diabetes, hypertension, altered tests, treatment and self-rated health. Logistic regression was used to analyze the associations. The prevalence of possible cases of FH was 0.96%, higher in women, between 45 and 59 years, white race/skin color and others, less education, people with diabetes, hypertension and total cholesterol ≥ 310 mg/dL. The presence of FH was positively associated with regular self-rated health (OR 1.96; 95% CI 0.99–3.84), poor/very poor (OR 3.02; 95% CI 1.30–7.03) and negatively with black race/skin color (OR 0.10; 95% CI 0.02–0.46) and complete elementary school, incomplete high school (OR 0.47; 95% CI 0.23–0.98) and complete high school and more (OR 0.45; 95% CI 0.21–0.95). FH affects 1:104 Brazilian adults, these findings contribute to understanding the burden of disease in Brazil. Due to the scarcity of studies on FH in low- and middle-income countries, further studies are desirable.

Genetic Spectrum and Cascade Screening of Familial Hypercholesterolemia in Routine Clinical Setting in Hong Kong.

Familial hypercholesterolemia (FH) is a prevalent but often underdiagnosed monogenic disorder affecting lipoprotein metabolism, and genetic testing for FH has not been widely conducted in Asia in the past. In this cross-sectional study of 31 probands (19 adults and 12 children) and an addition of 15 individuals (12 adults and 3 children), who underwent genetic testing and cascade screening for FH, respectively, during the period between February 2015 and July 2023, we identified a total of 25 distinct LDLR variants in 71.0% unrelated probands. Among the adult proband cohort, a higher proportion of genetically confirmed cases exhibited a positive family history of premature cardiovascular disease. Treatment intensity required to achieve an approximate 50% reduction in pretreatment low-density lipoprotein cholesterol (LDL-C) exhibited potentially better diagnostic performance compared to pretreatment LDL-C levels, Dutch Lipid Clinic Network Diagnostic Criteria (DLCNC) score, and modified DLCNC score. Adult individuals identified through cascade screening demonstrated less severe phenotypes, and fewer of them met previously proposed local criteria for FH genetic testing compared to the probands, indicating that cascade screening played a crucial role in the early detection of new cases that might otherwise have gone undiagnosed. These findings underscore the significance of genetic testing and cascade screening in the accurate identification and management of FH cases.

Detection of hidden cases of familial hypercholesterolemia in the Netherlands: a central laboratory data-driven strategy

Abstract Introduction Familial hypercholesterolemia (FH) is a common genetic disorder in which patients are at high risk for premature coronary artery disease (CAD) due to lifelong exposure to low-density lipoprotein cholesterol (LDL-C). Although early diagnosis and lipid lowering therapy (LLT) are essential to prevent adverse cardiovascular outcomes, FH patients remain globally underdiagnosed and undertreated, warranting novel screening methods to identify these patients. In the present study we aimed to evaluate whether existing central laboratory data can be utilized as a new method to detect undiagnosed FH patients. Additionally, we investigated the extent of underdiagnosis and undertreatment among patients with severe hypercholesterolemia in the Netherlands. Methods In this single-center, cross-sectional study, we selected individuals with at least one previously measured LDL-C plasma level ≥99.5th percentile for age and sex, from a central laboratory database containing lipid profiles of approximately 600.000 primary care patients. First, a blood sample was obtained to get more recent lipid values. Participating patients were subsequently asked to fill out a detailed questionnaire on medical and family history. Using these data, we calculated the Dutch Lipid Clinic Network (DLCN) criteria for each patient for the clinical diagnosis of FH. Results We identified a total of 5,100 patients with severe hypercholesterolemia (at least one LDL-C ≥99.5th percentile for age and sex) from the central laboratory database. Out of these, 1,206 patients (24%) participated in this study. Mean ± SD LDL-C corrected for LLT was 5.72 ± 1.83 mmol/L, 785 patients (65.1%) used LLT, and 150 patients (12.4%) had CVD in their medical history. In total, 131 patients (11%) had a persistent LDL-C ≥99.5th percentile for age and sex. DLCN criteria for phenotypic FH (DLCN score ≥6) were met by 302 patients (25%) of whom 39 patients (12.9%) had undergone prior genetic testing according to clinical guidelines. Of the 302 clinically diagnosed FH patients only 1 (0.3%) met the European Society of Cardiology (ESC) guideline recommending LDL-C targets &amp;lt;1.8 mmol/L in FH patients. Conclusion These data highlight the significant underdiagnosis and undertreatment of FH in the Netherlands, despite the fact that this country has a relatively high FH identification rate. We demonstrate that the use of central laboratory data is an effective strategy for identifying previously undetected cases of FH and eagerly await the genetic confirmation of the newly identified FH patients in this study, which will provide valuable insights into the genetic basis of this disorder and help further improve patient care.

Modelling a two-stage adult population screen for autosomal dominant familial hypercholesterolaemia: cross-sectional analysis within the UK Biobank

BackgroundMost people with autosomal dominant familial hypercholesterolaemia (FH) remain undetected, which represents a missed opportunity for coronary heart disease prevention.ObjectiveTo evaluate the performance of two-stage adult population screening for FH.DesignUsing...

Genetic backgrounds and diagnosis of familial hypercholesterolemia.

Lipid disorders play a critical role in the intricate development of atherosclerosis and its clinical consequences, such as coronary heart disease and stroke. These disorders are responsible for a significant number of deaths in many adult populations worldwide. Familial hypercholesterolemia (FH) is a genetic disorder that causes extremely high levels of LDL cholesterol. The most common mutations occur in genes responsible for low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), or proprotein convertase subtilisin/kexin type 9 (PCSK9). While genetic testing is a dependable method for diagnosing the disease, it may not detect primary mutations in 20%-40% of FH cases.

Long-term outcomes of liver transplantation for homozygous familial hypercholesterolaemia in Australia and New Zealand

Background and aimsHomozygous familial hypercholesterolaemia (FH) causes severe cardiovascular disease from childhood. Conventional drug therapy is usually ineffective; lipoprotein apheresis (LA) is often required. Liver transplantation (LT) can correct the metabolic defect but is considered a treatment of last resort. Newer drugs including lomitapide and evinacumab might reduce the need for apheresis and LT. We sought to determine the long-term outcomes following LT in Australia and New Zealand. MethodsWe analysed demographic, biochemical and clinical data from all patients in Australia and New Zealand who have received LT for homozygous FH, identified from the Australia and New Zealand Liver and Intestinal Transplant Registry. ResultsNine patients (five female; one deceased; seven aged between 3 and 6 years at the time of LT and two aged 22 and 26 years) were identified. Mean follow-up was 14.1 years (range 4–27). Baseline LDL-cholesterol off all treatment was 23 ± 4.1 mmol/L. Mean LDL-cholesterol on medical therapy (including maximal statin therapy in all patients, ezetimibe in three and LA in five) was 11 ± 5.7 mmol/L (p < 0.001). After LT, mean LDL-cholesterol was 2.6 ± 0.9 mmol/L (p = 0.004) with three patients remaining on statin therapy and none on LA. One patient died from acute myocardial infarction (AMI) three years after LT. Two patients required aortic valve replacement, more than 10 years after LT. The remaining six patients were asymptomatic after eight to 21 years of follow-up. No significant adverse events associated with immunosuppression were reported. ConclusionsLT for homozygous FH was highly effective in achieving substantial long-term reduction in LDL-cholesterol concentrations in all nine patients. LT remains an option for severe cases of homozygous FH where drug therapy combined with apheresis is ineffective or unfeasible.

Identification of c.683_684insCTGCAAGGACAAATCTGACGA pathogenic variant of the low-density lipoprotein receptor gene in a patient with familial hypercholesterolemia: a case report

Familial hypercholesterolemia (FH) is one of the most common monogenic diseases that leads to the early development of atherosclerosis and is characterized by a poor prognosis. However, only about 1% of FH cases are diagnosed in Russia. The aim of this study was to determine the genetic defect in the FH family and conduct DNA diagnostics in the proband relatives. The study was performed on blood samples obtained with the informed consent of the patients. Polymerase chain reaction and polyacrylamide gel electrophoresis were used. We report c.683_684insCTGCAAGGA CAAATCTGACGA pathogenic variant of the low-density lipoprotein receptor (LDLR) gene for the first time in Russia and demonstrate its cosegregation in a family with high blood cholesterol. The c.683_684in sCTGCAAGGACAAATCTGACGA insertion is considered as a probable cause of FH.

Possible explanations for the common clinical familial hypercholesterolemia phenotypes in the Faroe Islands

The prevalence of clinical familial hypercholesterolemia (FH) is very high in the Faroe Islands, but the possible causes are unknown. We aimed to describe potential genetic causes of FH in the Faroe Islands and to investigate whether levels of lipoprotein(a) and measures of dietary habits were associated with clinical FH in the Faroe Islands. In this case-control study, we identified potential clinical FH cases aged 18-75 years registered within a nationwide clinical laboratory database in the Faroe Islands and invited them for diagnostic evaluation according to clinical FH scoring systems. Controls were identified in the background population. Lipoprotein(a) was measured in plasma, while the fatty acid composition was determined in adipose tissue. The habitual diet of the participants was assessed using a food frequency questionnaire. Genetic testing for FH and polygenic variants was performed in a selection of clinical FH cases. A total of 121 clinical FH cases and 123 age- and sex-matched controls were recruited. We found a very low frequency of monogenic FH (2.5%), but a high level of polygenic FH (63%) in those genetically tested (67%). High levels of plasma lipoprotein(a) were associated with high odds of clinical FH. Clinical FH cases had a lower intake of saturated fatty acids (SFAs) measured by a high fat-score and a lower content of SFAs in adipose tissue compared with controls. The high prevalence of FH in the Faroe Islands may be due to polygenic causes of hypercholesterolemia and to a lesser extent other genetic factors and elevated plasma lipoprotein(a) levels.

Reducing Premature Coronary Artery Disease in Malaysia by Early Identification of Familial Hypercholesterolemia Using the Familial Hypercholesterolemia Case Ascertainment Tool (FAMCAT): Protocol for a Mixed Methods Evaluation Study.

Familial hypercholesterolemia (FH) is predominantly caused by mutations in the 4 FH candidate genes (FHCGs), namely, low-density lipoprotein receptor (LDLR), apolipoprotein B-100 (APOB-100), proprotein convertase subtilisin/kexin type 9 (PCSK9), and the LDL receptor adaptor protein 1 (LDLRAP1). It is characterized by elevated low-density lipoprotein cholesterol (LDL-c) levels leading to premature coronary artery disease. FH can be clinically diagnosed using established clinical criteria, namely, Simon Broome (SB) and Dutch Lipid Clinic Criteria (DLCC), and can be identified using the Familial Hypercholesterolemia Case Ascertainment Tool (FAMCAT), a primary care screening tool. This study aims to (1) compare the detection rate of genetically confirmed FH and diagnostic accuracy between the FAMCAT, SB, and DLCC in the Malaysian primary care setting; (2) identify the genetic mutation profiles, including novel variants, in individuals with suspected FH in primary care; (3) explore the experience, concern, and expectation of individuals with suspected FH who have undergone genetic testing in primary care; and (4) evaluate the clinical utility of a web-based FH Identification Tool that includes the FAMCAT, SB, and DLCC in the Malaysian primary care setting. This is a mixed methods evaluation study conducted in 11 Ministry of Health primary care clinics located at the central administrative region of Malaysia. In Work stream 1, the diagnostic accuracy study design is used to compare the detection rate and diagnostic accuracy of the FAMCAT, SB, and DLCC against molecular diagnosis as the gold standard. In Work stream 2, the targeted next-generation sequencing of the 4 FHCGs is used to identify the genetic mutation profiles among individuals with suspected FH. In Work stream 3a, a qualitative semistructured interview methodology is used to explore the experience, concern, and expectation of individuals with suspected FH who have undergone genetic testing. Lastly, in Work stream 3b, a qualitative real-time observation of primary care physicians using the "think-aloud" methodology is applied to evaluate the clinical utility of a web-based FH Identification Tool. The recruitment for Work stream 1, and blood sampling and genetic analysis for Work stream 2 were completed in February 2023. Data collection for Work stream 3 was completed in March 2023. Data analysis for Work streams 1, 2, 3a, and 3b is projected to be completed by June 2023, with the results of this study anticipated to be published by December 2023. This study will provide evidence on which clinical diagnostic criterion is the best to detect FH in the Malaysian primary care setting. The full spectrum of genetic mutations in the FHCGs including novel pathogenic variants will be identified. Patients' perspectives while undergoing genetic testing and the primary care physicians experience in utilizing the web-based tool will be established. These findings will have tremendous impact on the management of patients with FH in primary care and subsequently reduce their risk of premature coronary artery disease. DERR1-10.2196/47911.

Identification of pathogenic variants in the Brazilian cohort with Familial hypercholesterolemia using exon-targeted gene sequencing

Familial hypercholesterolemia (FH) is a monogenic disease characterized by high plasma low-density lipoprotein cholesterol (LDL-c) levels and increased risk of premature atherosclerotic cardiovascular disease. Mutations in FH‐related genes account for 40% of FH cases worldwide. In this study, we aimed to assess the pathogenic variants in FH-related genes in the Brazilian FH cohort FHBGEP using exon-targeted gene sequencing (ETGS) strategy. FH patients (n = 210) were enrolled at five clinical sites and peripheral blood samples were obtained for laboratory testing and genomic DNA extraction. ETGS was performed using MiSeq platform (Illumina). To identify deleterious variants in LDLR, APOB, PCSK9, and LDLRAP1, the long-reads were subjected to Burrows-Wheeler Aligner (BWA) for alignment and mapping, followed by variant calling using Genome Analysis Toolkit (GATK) and ANNOVAR for variant annotation. The variants were further filtered using in-house custom scripts and classified according to the American College Medical Genetics and Genomics (ACMG) guidelines. A total of 174 variants were identified including 85 missense, 3 stop-gain, 9 splice-site, 6 InDel, and 71 in regulatory regions (3′UTR and 5′UTR). Fifty-two patients (24.7%) had 30 known pathogenic or likely pathogenic variants in FH-related genes according to the American College Medical and Genetics and Genomics guidelines. Fifty-three known variants were classified as benign, or likely benign and 87 known variants have shown uncertain significance. Four novel variants were discovered and classified as such due to their absence in existing databases. In conclusion, ETGS and in silico prediction studies are useful tools for screening deleterious variants and identification of novel variants in FH-related genes, they also contribute to the molecular diagnosis in the FHBGEP cohort.

Concurrent Living Donor Liver Transplantation and Off-Pump Coronary Artery Bypass in a Five-Year-Old Child With Homozygous Familial Hypercholesterolemia: A Case Report

Homozygous familial hypercholesterolemia (FH) is a rare disease that causes serious cardiovascular problems and may be fatal even at an early age. Because this disease variant is rather aggressive, the effect of lipid-lowering agents and lipid apheresis remains inadequate in most cases. In patients who are not responding or tolerating available treatments, liver transplantation (LT) is the last and definitive solution. In addition to LT, the need for cardiac surgery is often substantial. This study presents the first pediatric case of FH who underwent off-pump coronary artery bypass (OPCAB) surgery concurrent with live-donor LT (LDLT). The early postoperative period was uneventful. After a 1-year follow-up period, the patient is alive and well with normal liver functions and cholesterol levels remaining within the normal range without any lipid-lowering medical therapy. Performing simultaneous coronary bypass and LT may be safe and feasible even for pediatric patients.

Targeted sequencing of a gene panel in patients with familial hypercholesterolemia from Southern Poland.

Familial hypercholesterolemia (FH) is an autosomal dominant monogenic lipid metabolism disorder characterized by a significantly elevated level of low‑density lipoprotein (LDL) cholesterol and leading to premature ischemic heart disease. FH is caused by mutations in the LDLR, APOB, and PCSK9 genes; however, these mutations account for only about 40% of FH cases. In order to obtain a genetic diagnosis of FH, sequencing of other genes involved in the lipid metabolism might be useful. This study aimed to describe genetic variants in genes associated with FH in a group of patients from the Małopolska province in Southern Poland, using the targeted next generation sequencing (NGS) technology. The study involved 90 unrelated adults (age range, 18-70 years) with FH diagnosed clinically according to the Simon Broome Register criteria. A custom‑designed capture assay and the Illumina MiSeq platform were used. The panel included exons and exon / intron boundaries of known FH‑causing genes: LDLR, APOB, and PCSK9, as well as genes previously associated with high cholesterol levels: APOE, ABCG5, ABCG8, LPL, NPC1, LDLRAP1, LIPC, STAP1, and CELSR2. Genetic variants were classified based on in silico predictions and ClinVar reports. We detected 4 patients with variants in the LDLR and APOB genes that had not been previously linked to FH in ClinVar. We also found APOB mutations outside the common LDL receptor-binding region, in exons 26 and 29. Interestingly, we observed a high frequency of pathogenic variants in exon 4 of the APOE gene: rs7412, probably damaging (4 patients) and rs429358, benign (16 patients). NGS is a useful and reliable method to detect new variants in genes related to FH. In addition, the results enable the detection of FH phenocopies and introduction of appropriate treatment.

Anaesthesia management in paediatric liver transplantation in two siblings in the rare case of familial hypercholesterolemia, one of them post CABG

Anaesthesia management in paediatric liver transplantation in two siblings in the rare case of familial hypercholesterolemia, one of them post CABG

Subclinical atherosclerosis determined by coronary artery calcium deposition in patients with clinical familial hypercholesterolemia

Background and aimsLimited knowledge exists regarding the association between coronary artery calcium (CAC) deposition in patients with clinical familial hypercholesterolemia (FH) and FH subtypes such as polygenic causes. We studied CAC score in patients with clinical FH and subtypes including polygenic causes of FH compared to healthy controls. MethodsIn a case-control study, we identified potential clinical FH cases registered with an LDL-C >6.7 mmol/l within a nationwide clinical laboratory database on the Faroe Islands and invited them for diagnostic evaluation according to clinical FH scoring systems. Controls were identified in the background population. All subjects were aged 18–75 years and without a history of cardiovascular disease. FH mutation testing and genotypes of twelve LDL-C associated single nucleotide polymorphisms were determined using conventional methods in selected individuals. CAC scores were assessed by cardiac CT. Odds ratios obtained using multivariate logistic regression were used as measures of association. ResultsA total of 120 clinical FH patients and 117 age- and sex-matched controls were recruited. We found a very low frequency of monogenic FH (3%), but a high level of polygenic FH (60%) in those genetically tested (54%). There was a statistically significant association between the CAC score and a diagnosis of clinical FH with the highest observed odds ratio of 5.59 (95% CI 1.65; 18.94, p = 0.006) in those with a CAC score ≥300 compared to those with a CAC of zero. In supplemental analyses, there was a strong association between CAC scores and clinical FH of a polygenic cause. ConclusionWe found a statistically significant association between CAC levels and clinical FH with the highest observed risk estimates among clinical FH cases of a presumed polygenic cause.

Clinical characteristics of sitosterolemic children with xanthomas as the first manifestation

Background:Sitosterolemia (STSL) is an extremely rare genetic disease. Xanthomas as the first symptom are frequently misinterpreted as familial hypercholesterolemia (FH) in children. Inappropriate treatment may deteriorate the condition of STSL.Objectives:To present the clinical and laboratory characteristics of xanthomatous children diagnosed with sitosterolemia in comparison with childhood FH with xanthomas.Methods:We summarized and compared the clinical characteristics of STSL and FH patients with xanthomas as the first manifestations and investigated the different indicators between the STSL and FH groups, as well as their diagnostic values for STSL.Results:Two tertiary pediatric endocrinology departments contributed ten STSL cases. Five of the STSL patients (50%) experienced mild anemia, whereas two (20%) had vascular complications. The xanthomas of the STSL group displayed morphologies comparable to those of the FH group. There were ten cases of homozygous FH (HoFH) with xanthomas as the predominant symptom of the control group who had no anemia. The serum cholesterol (Chol) levels of the STSL and FH groups were 12.57 (9.55 ~ 14.62) mmol/L and 17.45 (16.04 ~ 21.47) mmol/L, respectively (p value 0.002). The serum low-density lipoprotein cholesterol (LDL-c) levels of the STSL and FH groups were 9.26 ± 2.71 mmol/L and 14.58 ± 4.08 mmol/L, respectively (p value 0.003). Meanwhile, the mean platelet volume (MPV) levels of the STSL and FH groups were 11.00 (9.79 ~ 12.53) fl. and 8.95 (8.88 ~ 12.28) fl., respectively (p value 0.009). The anemia proportions of the STSL and FH groups were 50% and 0%, respectively (p value 0.033). The AUC values of Chol, LDL-c, MPV, hemoglobin (Hb) for the diagnosis of STSL were 0.910, 0.886, 0.869, 0.879, respectively. Chol ≤ 15.41 mmol/L, LDL-c ≤ 13.22 mmol/L, MPV ≥ 9.05 fl., or Hb≤120 g/L were the best thresholds for diagnosing STSL with childhood xanthomas.ConclusionThe xanthoma morphology of STSL patients resembles that of FH patients. Xanthomas as the initial symptom of a child with Chol ≤ 15.41 mmol/L, LDL-c≤13.22 mmol/L, MPV ≥ 9.05 fl., or Hb≤120 g/L, he was most likely to have STSL.