Pediatric Summary Report

Secondary Findings in Pediatric Subjects

Non-diagnostic, excludes newborn screening & prenatal testing/screening

• Status (Pediatric): Passed (Consensus scoring is Complete)
• Curation Status (Pediatric): Released 1.0.3
• Status (Adult): Passed (Consensus scoring is Complete)
• GENE/GENE PANEL: LDLR, APOB, PCSK9
• Condition: Homozygous Familial Hypercholesterolemia
• Mode(s) of Inheritance: Semidominant inheritance

Actionability Assertion

• LDLR ⇔ 0007750 (hypercholesterolemia, familial, 1): Strong Actionability
• APOB ⇔ 0007751 (hypercholesterolemia, autosomal dominant, type b): Strong Actionability
• PCSK9 ⇔ 0011369 (hypercholesterolemia, autosomal dominant, 3): Strong Actionability

Actionability Rationale

All experts agreed with the assertion computed according to the rubric. The assertion is not definitive because the condition is so severe that even with the intervention the baseline events will still occur. In addition, the condition is rare in children so the evidence is based on small numbers.

Final Consensus Scores

Gene Condition Pairs: LDLR ⇔ 0007750 (OMIM:143890) APOB ⇔ 0007751 (OMIM:144010) PCSK9 ⇔ 0011369 (OMIM:603776)

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of the Intervention	Total Score
Clinical cardiovascular events / Lipid lowering medications and diet to FH appropriate LDL-C goal	2	3C	2A	2	9CA
Clinical cardiovascular events / Lipid lowering therapy (including apheresis) to FH appropriate LDL-C goal	2	3C	3A	2	10CA

1. What is the nature of the threat to health for an individual carrying a deleterious allele?

Prevalence of the Genetic Condition

The frequency of homozygous familial hypercholesterolemia (HoFH) has historically been estimated to be 1/1,000,000, though genetically isolated subpopulations have higher rates from 1/30,000 to 1/100,000. Recent estimates from general population studies are 1/160,000 to 1/300,000. [1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12]

Clinical Features

The clinical features of HoFH are characterized by extensive xanthomas, premature and progressive cardiovascular disease (CVD), and total cholesterol >500 mg/dL. The major clinical manifestations of FH result from prolonged exposure to high levels of LDL-C leading to the development of atherosclerotic lesions in the heart, brain, and peripheral arteries. Aggressive atherosclerosis of the aortic root occurs, primarily affecting the aortic valve and supravalvular region. Atherosclerosis leads to an increased risk of cardiovascular disease (CVD), most commonly coronary artery disease (CAD). CAD may manifest as symptoms of ischemia (e.g., angina) due the restriction of blood flow; however acute complications such as myocardial infarction (MI) and sudden cardiac death can occur as the first manifestations. Dyspnea, diastolic and systolic left ventricle heart failure, and severe aortic stenosis are common. Xanthomas around the tendons and interdigital folds may occur leading to tendinitis and joint pain. [2, 3, 5, 13, 7, 8, 10, 14, 15]

Natural History

HoFH commonly presents as physical manifestations in infancy and early childhood, consisting primarily of fleshy cutaneous and tendinous xanthomata, most marked in the Achilles tendon. Clinical CVD events begin as early as the first decade of life, but usually manifest by the second decade, consisting primarily of coronary ostial stenoses and occlusions, aortic valve thickening with stenosis and/or regurgitation, and extensive atherosclerosis of the aortic root. Untreated, most individuals with HoFH develop severe CAD and aortic stenosis before age 20 and die before age 30. Children as young as 4 years of age have suffered sudden death due to acute MI. The rate of either death or coronary bypass surgery by the teenage years is high. HoFH patients who are LDLR-defective (2-25% residual enzyme activity) have a better prognosis than those who are receptor negative (<2% enzyme activity). [2, 3, 4, 16, 5, 6, 13, 7, 8, 9, 10, 11]

2. How effective are interventions for preventing harm?

Patient Management

The American College of Medical Genetics and Genomics (ACMG) has developed an ACT sheet to help clinical decision-making when pathogenic variant(s) in APOB, LDLR, and/or PCSK9 are identified as a secondary finding: https://www.acmg.net/PDFLibrary/Familial-Hypercholesterolemia.pdf

Patients should be urgently referred to specialized care at the time of diagnosis and have a complete cardiovascular evaluation, as fatal coronary artery occlusions have been reported before 2 years of age. (Tier 1) [2, 10]

Conventional risk factors for atherosclerotic CVD (ASCVD) such as age, sex, HDL-C, hypertension, smoking, lipoprotein(a), and diabetes should be ascertained in patients with FH. Existing risk calculators for the general population (Framingham Risk Score, Pooled Cohort Equation, European SCORE) may underestimate the risk in patients with FH. If adult patients with FH require further stratification of their ASCVD risk, the Montreal-FH-SCORE (MFHS) may be used, which was developed to stratify risk in FH and is based on age, HDL-C, gender, hypertension, and smoking status. A validation study of the MFHS in 718 adults with FH indicated that patients with a high score had a significant 8.8-fold (95% CI: 5.8-13.3) increased risk of a CVD event compared to patients with a low score. (Tier 1) [2]

Treatment for HoFH should be undertaken within a lipid specialist center. Children with HoFH should be managed by a medical care team (pediatricians specializing in diabetes and/or endocrinology, lipid specialists, geneticists, dieticians, and psychologists) with expertise in FH in an appropriate child-focused setting. (Tier 2) [2, 3, 4, 6, 10, 17, 18, 19, 20, 21]

A personalized pharmacologic treatment plan considering age, additional cardiovascular risk factors, psychosocial and socioeconomic factors, and personal as well as family preferences, should be developed as a shared decision process. (Tier 1) [2, 19]

The initial treatment for individuals with FH, irrespective of their calculated cardiovascular risk, should be a high intensity statin. Statin therapy is recommended to be initiated by 8-12 years of age; however, HoFH patients under the age of 8-10 years with high-risk family history, high-risk conditions, or multiple risk factors might be considered for medication initiation at a younger age. Target serum LDL-C concentrations have not been established for children, but in adults, the goal should be a reduction of at least 50% in LDL-C concentration from baseline. Statin treatment is lifelong. A meta-analysis of 6 studies (669 children with HeFH) estimated that statins lowered LDL-C by an additional 32.2% (95% CI: 29.4-34.9%) over placebo at 48-week follow-up. No studies have reported the impact of statins vs placebo on clinical outcomes in adults with FH. However, high and moderate quality RCTs from adult populations without FH have found that high-intensity statins reduce non-fatal MI (relative risk [RR]: 0.46, 95% CI: 0.37-0.59). Statins have also been shown to have a small (but non-clinically important) effect on reducing 5-year all-cause mortality (RR: 0.90, 95% CI: 0.80-1.00), CV mortality (RR: 0.73, 95% CI: 0.61-0.88), and stroke (RR: 0.80, 95% CI: 0.70-0.91). (Tier 1) [10, 19, 22, 23, 24]

Based on a meta-analysis of 4 retrospective observational studies, individuals with HeFH of all ages in the pre-statin era (defined as before 1987) exhibited a higher risk for stroke compared with the general population (2 studies of 629 patients with HeFH; OR: 7.66, 95% CI: 6.06-9.68) but a lower odds for stroke following the generalization of statin therapy (2 studies of 2745 patients with HeFH; OR: 0.25, 95% CI: 0.18-0.36). (Tier 1) [25]

Ezetimibe, as a monotherapy or in combination with statin therapy, is recommended as an option for treating HoFH in patients in whom initial statin therapy is contraindicated or not tolerated or when LDL-C levels are not controlled by statins alone. An RCT of 50 children and adults with HoFH showed that ezetimibe plus statin reduced LDL-C levels compared to statin alone (20.7% vs 6.7 % reduction, respectively; p<0.01). An RCT of 248 patients aged 10-17 years with HeFH found that ezetimibe plus simvastatin reduced LDL-C compared to simvastatin alone (49.5% vs 34.4%, respectively; p<0.01). No trials of ezetimibe in individuals with FH have reported on clinical outcomes. In non-FH individuals, an RCT (IMPROVE-IT trial) of 18,144 adult patients with stabilized acute coronary syndrome found a 6.4% relative risk reduction at 6 years for the primary endpoint (a composite of cardiovascular death, major coronary event, or non-fatal stroke) with use of ezetimibe plus simvastatin compared with simvastatin alone (hazard ratio [HR]: 0.94, 95% CI: 0.89-0.99). (Tier 1) [2, 19, 23]

Patients with FH and intolerance or contraindications to statins or ezetimibe should be considered for treatment with either a bile acid sequestrant (resin) or a fibrate. RCTs have found that bile acid sequestrants (6 RCTs, N= 248 adult and N=214 pediatric patients with FH) and fibrates (3 RCTs, N= 208 adult and N=14 pediatric patients with FH) can result in similar reductions in LDL-C and total cholesterol compared to placebo as treatment with statins. (Tier 1) [10, 19, 23]

There is ongoing research on newer pharmacotherapeutic agents including PCSK9 inhibitors (Alirocumab and Evolocumab), MTP inhibitors (lomitapide) and antisense oligonucleotides (mipomersen) and their role as primary therapies patients with HoFH. [3, 6, 13, 17, 20, 26, 27, 28, 29, 30, 31]

LDL-C apheresis should be offered for treatment of HoFH with initiation based on response to lipid-lowering therapy (LLT), the presence of CHD, and child weight (>15kg). For children, treatment can be performed as early as technically feasible (before age 5 and at least by age 8) and must be under the care of lipid specialists in academic medical centers with this expertise. (Tier 1) [2, 10, 19]

A systematic review of 7 pre-post observational studies of apheresis in HoFH (N= 61) found mean reductions in LDL-C levels from 57-76% in patients of all ages. Two of these studies (n=39) reported that after extended follow up, the mean reduction was around 34-36%. Data from 34 adults with FH receiving apheresis for an average of 2.5 years found that after apheresis individuals had a 3.2-fold decrease in CV events and over a 20-fold decrease in cardiovascular interventions. Subjectively, individuals reported decreased episodes of angina and improved quality of life. (Tier 1) [12]

Data from the German Lipoprotein Apheresis Registry, based on over 15,000 apheresis procedures in 1279 both FH and non-FH adults performed through 2015, showed a median acute reduction in LDL-cholesterol of 69% in hyperlipidemic patients with CVD and a 97% decrease in the incidence of major adverse coronary events during the first year of lipoprotein apheresis compared with the 2 years preceding the start of this treatment. In addition, a French study of 20 children with HoFH showed that the frequency of aortic stenosis and need for surgery were associated with the age at which lipoprotein apheresis was initiated, where those with aortic root atheroma started apheresis at age 10 whereas those without atheroma had started it earlier, at age 5. (Tier 5) [32]

Daily oral aspirin may be considered to prevent atherothrombosis in asymptomatic adults and adolescents aged 16 and older. In pediatric patients, aspirin may be considered with caution. No studies of aspirin in FH were identified. In patients with HoFH who have not had a cardiovascular event, a net benefit of aspirin is a reasonable assumption because atheromatous disease is inevitable. (Tier 2) [3, 6, 7, 33]

An analysis of 6 primary prevention trials of non-FH individuals of low average vascular disease risk found aspirin, compared to placebo, reduced serious vascular events (RR: 0.88, 95% CI: 0.82-0.94), due mainly to a reduction in non-fatal MI (RR: 0.77, 95% CI: 0·67–0·89); the effect on stroke and mortality were not significant. Analysis of 16 secondary prevention trials of non-FH individuals of high average vascular disease risk found aspirin yielded a greater absolute reduction in serious vascular events (RR: 0.81, 95% CI: 0.75-0.87), stroke (RR: 0.81, 95% CI: 0.71-0.92), major coronary events (RR: 0.80, 95% CI: 0.73-0.88), and total mortality (RR: 0.90, 95% CI: 0.82-0.99). (Tier 2) [6]

Lifestyle advice should be provided as a component of medical management, and not a substitute for LLT, including: individualized nutritional advice and physical activity advice, limiting alcohol consumption, stress reduction, and support for weight loss and decreases in blood pressure and glucose levels in line with national guidance for the general population. The aim of these interventions is not to lower LDL-C, but to confer a cardioprotective effect. However, there is no evidence that these interventions improve clinical outcomes in patients with FH. (Tier 2) [2, 3, 4, 6, 7, 9, 11, 13, 14, 16, 19, 20, 21, 22, 33, 34, 35, 36, 37, 38, 39]

Dietary modifications may be started after 2 years of age and should be under the supervision of a dietician or nutritionist for children and young adults. Foods containing plant stanols and sterols may be added to the diet but must be taken consistently to be effective. A systematic review (6 RCTs, N=124 HeFH patients) as well as 3 additional RCTs (ranging from 18-42 FH patients of all ages, 4-12 weeks follow-up) found significant reductions in LDL-C of 0.48-0.69 mmol/l (9.2-10.2%) in both children and adults with FH consuming plant sterol and stanol enriched foods. (Tier 2) [7, 11, 14, 16, 18, 19, 20, 21, 33, 34, 35, 36, 38]

Patients should be taught “red flag” symptoms of CVD and acute coronary events. (Tier 2) [6]

Psychological support (including family support) should be part of routine care. (Tier 2) [3]

The lipid team should be involved if a patient is hospitalized. An alert card with contact details should be issued. (Tier 2) [6]

Non-hormonal contraceptive techniques are recommended. If essential, oral contraceptives with the lowest thrombotic risk should be selected. (Tier 2) [3, 6]

Women should be advised that pregnancy in HoFH is hazardous due to the aggravation of hypercholesterolemia due to discontinuation of pharmacotherapy coupled with the effects of high levels of estrogen and progesterone on lipoprotein metabolism. Pre-conception counseling and shared-care arrangements should include expertise in cardiology, lipidology and obstetrics. Pre-conception, women should be referred to a cardiologist for a detailed cardiovascular assessment, including the aortic valve and root, and evaluation of arteriosclerosis status. (Tier 2) [3, 6, 19, 21, 22, 33, 34, 36, 37]

Surveillance

All people with FH should be offered a regularly structured review that is carried out every 6-12 months including an update of family pedigree, changes in CHD status of relatives, assessment of any symptoms of CHD, smoking status, fasting lipid profile, discussion about concordance with medication, possible side effects of treatment, and changes in lifestyle or LLT that may be required. Children should also be assessed for weight, growth, and developmental milestones. (Tier 2) [6, 9, 19, 14, 33]

Frequent surveillance with cardiovascular imaging and stress testing is necessary to detect and monitor progression of atherosclerosis and valvular diseases, which may progress even when cholesterol levels are reduced. Evaluations should include a patient interview and physical examination; a medical questionnaire and imaging to evaluate coronary and peripheral artery disease (CAD and PAD; especially the carotid), aortic stenosis, aortic aneurisms, and valvular disorders. In children, non-invasive imaging is preferable. For adults, evaluations should be repeated every 6 months with subsequent Doppler echocardiographic evaluation of the heart and aorta annually, stress testing and, if available, computed tomography coronary angiography every 5 years or more frequently if needed. For children with HoFH, frequency of evaluations should be based on the age of the child, disease severity, and presence of CVD risk factors. (Tier 2) [2, 3, 6, 34, 35, 37, 9, 10, 19, 20, 21]

Circumstances to Avoid

Individuals with FH should be strongly discouraged from smoking or advised to stop smoking given the greatly increased risk for CHD. In patients with FH, LDL-C catabolism is slow and LDL-C is susceptible to oxidization. In smokers, children and adults with FH and CAD flow mediated dilatation was reduced or absent (p<0.001) compared to controls. (Tier 2) [2, 4, 7, 34, 35, 37, 9, 19, 11, 38, 14, 21]

3. What is the chance that this threat will materialize?

Mode of Inheritance

Semidominant inheritance

Prevalence of Genetic Variants

Population screening of 50,762 individuals in a US health care system identified pathogenic variants associated with FH in 1:256 in unselected individuals; however, this may be an overestimate as it was based on screening within a single health care delivery system. None of these cases were homozygous of compound heterozygous for pathogenic variants. (Tier 3) [40]

Penetrance

In a case series of 17 patients with HoFH, magnetic resonance imaging of the aortic root identified atherosclerotic plaques in 53% of patients and supravalvular aortic stenosis in 41%. (Tier 3) [41]

An analysis of individuals identified from cascade screening identified 49 patients with HoFH (20 were true homozygous, 25 were compound heterozygous). Within this population, 50% of the patients met the clinical criteria for HoFH (LDL-C > 13.0 mmol/L) and 29% had a recorded history of a CVD event. (Tier 5) [42]

About 79% of the pathogenic variants in the LDLR gene are likely expressed as a hypercholesterolemic phenotype. (Tier 3) [21]

Relative Risk

No information related to relative risk was identified related to HoFH.

Expressivity

There is a wide variation in age of onset and speed of progression in CAD among FH patients. (Tier 3) [34]

Individuals with FH develop aortic calcifications in a gene-dosage and age-dependent manner. (Tier 3) [2]

In FH, the expression of ischemic heart disease remains variable, ranging from severe premature disease in up to 10% of affected individuals by 40 years of age to the absence of cardiovascular disease until late in life in a similarly small percentage. (Tier 4) [13]

4. What is the Nature of the Intervention?

Nature of Intervention

Interventions for HoFH include biochemical surveillance, invasive and non-invasive cardiac imaging, medication use, and apheresis. Statins are generally well-tolerated. Adverse effects are rare even at standard doses, but include elevated liver enzymes, muscle symptoms (the most severe of which is rhabdomyolysis, which can be fatal), new onset diabetes, potential fetal teratogenicity, and impacts on sexual and physical maturation. A recent systematic review and meta-analysis of statin therapy in almost 800 children with FH did not find any statistically significant differences between statin- and placebo-treated children for the occurrence of adverse events, sexual development, muscle toxicity, or liver toxicity. There was a minimal difference in growth in favor of the statin group. Apheresis typically needs to be undertaken approximately every two weeks (though frequency can vary) and requires invasive and/or long-term vascular access, specialist administration, likely anticoagulation, and monitoring with the duration of the procedure ranging from 2 to >3 hours. Serious adverse events are rare, with the most common reactions being light-headedness, nausea/vomiting, hypotension, and chest pain. Because of the demands of apheresis, psychological status and quality of life should be monitored in all patients. Adverse reactions with ezetimibe monotherapy are usually mild and transient and include gastrointestinal symptoms (e.g., abdominal pain) and fatigue; when taken with a statin adverse events may include elevated liver enzymes, headache, and myalgia. Aspirin can, in rare cases, lead to gastrointestinal and extracranial bleeds in patients of all ages, and Reye’s syndrome in children. Adverse effects of bile acid sequestrants are gastrointestinal (bloating, nausea, diarrhea, and constipation) which significantly affect compliance; as well as malabsorption of fat-soluble vitamins (A, D, E) and some medications. [43, 3, 6, 22, 8, 9, 10, 19, 44, 45, 24, 12, 20, 33, 21]

5. Would the underlying risk or condition escape detection prior to harm in the setting of recommended care?

Chance to Escape Clinical Detection

Many patients with FH remain unrecognized, particularly in countries that have not enacted a national registry. (Tier 3) [2]

The majority of children and adolescents with FH are undiagnosed, as symptoms and signs only develop after decades of hypercholesterolemia. (Tier 4) [9]

HoFH is typically diagnosed when considerable CAD has already developed. (Tier 3) [3]

Date of Search: 02.27.2020 (updated 08.03.2020)

Reference List

1. Banach M, Jankowski P, Jóźwiak J, Cybulska B, Windak A, Guzik T, Mamcarz A, Broncel M, Tomasik T, Rysz J, Jankowska-Zduńczyk A, Hoffman P, Mastalerz-Migas A. PoLA/CFPiP/PCS Guidelines for the Management of Dyslipidaemias for Family Physicians 2016. Arch Med Sci. (2017) 13(1734-1922):1-45.

2. Brunham LR, Ruel I, Aljenedil S, Rivière JB, Baass A, Tu JV, Mancini GBJ, Raggi P, Gupta M, Couture P, Pearson GJ, Bergeron J, Francis GA, McCrindle BW, Morrison K, St-Pierre J, Henderson M, Hegele RA, Genest J, Goguen J, Gaudet D, Paré G, Romney J, Ransom T, Bernard S, Katz P, Joy TR, Bewick D, Brophy J. Canadian Cardiovascular Society Position Statement on Familial Hypercholesterolemia: Update 2018. Can J Cardiol. (2018) 34(1916-7075):1553-1563.

3. Cuchel M, Bruckert E, Ginsberg HN, Raal FJ, Santos RD, Hegele RA, Kuivenhoven JA, Nordestgaard BG, Descamps OS, Steinhagen-Thiessen E, Tybjaerg-Hansen A, Watts GF, Averna M, Boileau C, Boren J, Catapano AL, Defesche JC, Hovingh GK, Humphries SE, Kovanen PT, Masana L, Pajukanta P, Parhofer KG, Ray KK, Stalenhoef AF, Stroes E, Taskinen MR, Wiegman A, Wiklund O, Chapman MJ. 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):2146-57.

4. Daniels SR, Gidding SS, de Ferranti SD. Pediatric aspects of familial hypercholesterolemias: recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin Lipidol. (2011) 5(1933-2874):S30-7.

5. E Youngblom, JW Knowles. Familial Hypercholesterolemia. 2014 Jan 02. In: RA Pagon, MP Adam, HH Ardinger, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: http://www.ncbi.nlm.nih.gov/books/NBK174884

6. France M, Rees A, Datta D, Thompson G, Capps N, Ferns G, Ramaswami U, Seed M, Neely D, Cramb R, Shoulders C, Barbir M, Pottle A, Eatough R, Martin S, Bayly G, Simpson B, Halcox J, Edwards R, Main L, Payne J, Soran H. HEART UK statement on the management of homozygous familial hypercholesterolaemia in the United Kingdom. Atherosclerosis. (2016) 255:128-139.

7. Goldberg AC, Hopkins PN, Toth PP, Ballantyne CM, Rader DJ, Robinson JG, Daniels SR, Gidding SS, de Ferranti SD, Ito MK, McGowan MP, Moriarty PM, Cromwell WC, Ross JL, Ziajka PE. Familial hypercholesterolemia: screening, diagnosis and management of pediatric and adult patients: clinical guidance from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin Lipidol. (2011) 5(3 Suppl):S1-8.

8. Mach, F.; Baignet, C.; Catapano, A.L.; Koskinas, K.C.; Casula, M.; Badimon, L.; Chapman, M.J.; De Backer, G.G.; Delgado, V.; Ference, B.A.; Graham, I.M.; Halliday, A.; Landmesser, U.; Mihaylova, B.; Pedersen, T.R.; Riccardi, G.; Richter, D.J.; Sabatine, M.S.; Taskinen, M.; Tokgozoglu, L.; Wiklund, O. 2019 ESC/EAS guidelines for the management of dyslipidaemias: Lipid modification to reduce cardiovascular risk. Atherosclerosis. (2019) Accessed: 2020-08-03. Website: https://www.sciencedirect.com/science/article/pii/S0021915019314595?via%3Dihub

9. Martin AC, Coakley J, Forbes DA, Sullivan DR, Watts GF. Familial hypercholesterolaemia in children and adolescents: a new paediatric model of care. J Paediatr Child Health. (2013) 49(1440-1754):E263-72.

10. National Heart, Lung, and Blood Institute. Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents. (2012) Accessed: 2020-08-03. Website: https://www.nhlbi.nih.gov/health-topics/integrated-guidelines-for-cardiovascular-health-and-risk-reduction-in-children-and-adolescents

11. Nordestgaard BG, Chapman MJ, Humphries SE, Ginsberg HN, Masana L, Descamps OS, Wiklund O, Hegele RA, Raal FJ, Defesche JC, Wiegman A, Santos RD, Watts GF, Parhofer KG, Hovingh GK, Kovanen PT, Boileau C, Averna M, Boren J, Bruckert E, Catapano AL, Kuivenhoven JA, Pajukanta P, Ray K, Stalenhoef AF, Stroes E, Taskinen MR, Tybjaerg-Hansen A. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society. Eur Heart J. (2013) 34(45):3478-90a.

12. Wang A, Richhariya A, Gandra SR, Calimlim B, Kim L, Quek RG, Nordyke RJ, Toth PP. Systematic Review of Low-Density Lipoprotein Cholesterol Apheresis for the Treatment of Familial Hypercholesterolemia. J Am Heart Assoc. (2016) 5(7).

13. Gidding SS, Champagne MA, de Ferranti SD, Defesche J, Ito MK, Knowles JW, McCrindle B, Raal F, Rader D, Santos RD, Lopes-Virella M, Watts GF, Wierzbicki AS. The Agenda for Familial Hypercholesterolemia: A Scientific Statement From the American Heart Association. Circulation. (2015) 132(22):2167-92.

14. Rynkiewicz A, Cybulska B, Banach M, Filipiak K, Guzik T, Idzior-Walus B, Imiela J, Jankowski P, Klosiewicz-Latoszek L, Limon J, Mysliwiec M, Opolski G, Steciwko A, Stepinska J, Zdrojewski T. Management of familial heterozygous hypercholesterolemia: Position Paper of the Polish Lipid Expert Forum. J Clin Lipidol. (2013) 7(3):217-21.

15. Wong B, Kruse G, Kutikova L, Ray KK, Mata P, Bruckert E. Cardiovascular Disease Risk Associated With Familial Hypercholesterolemia: A Systematic Review of the Literature. Clin Ther. (2016) 38(7):1696-709.

16. Descamps OS, Tenoutasse S, Stephenne X, Gies I, Beauloye V, Lebrethon MC, De Beaufort C, De Waele K, Scheen A, Rietzschel E, Mangano A, Panier JP, Ducobu J, Langlois M, Balligand JL, Legat P, Blaton V, Muls E, Van Gaal L, Sokal E, Rooman R, Carpentier Y, De Backer G, Heller FR. Management of familial hypercholesterolemia in children and young adults: consensus paper developed by a panel of lipidologists, cardiologists, paediatricians, nutritionists, gastroenterologists, general practitioners and a patient organization. Atherosclerosis. (2011) 218(1879-1484):272-80.

17. Lloyd-Jones DM, Morris PB, Ballantyne CM, Birtcher KK, Daly DD, DePalma SM, Minissian MB, Orringer CE, Smith SC. 2017 Focused Update of the 2016 ACC Expert Consensus Decision Pathway on the Role of Non-Statin Therapies for LDL-Cholesterol Lowering in the Management of Atherosclerotic Cardiovascular Disease Risk: A Report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways. J. Am. Coll. (Cardiol)

18. Myśliwiec M, Walczak M, Małecka-Tendera E, Dobrzańska A, Cybulska B, Filipiak K, Mazur A, Jarosz-Chobot P, Szadkowska A, Rynkiewicz A, Chybicka A, Socha P, Brandt A, Bautembach-Minkowska J, Zdrojewski T, Limon J, Gidding SS, Banach M. Management of familial hypercholesterolemia in children and adolescents. Position paper of the Polish Lipid Expert Forum. (J) 8(1933-2874):173-80.

19. National Institute for Health and Care Excellence. Familial hypercholesterolaemia: identification and management. (2019) Accessed: 2020-08-03. Website: https://www.nice.org.uk/guidance/cg71

20. Watts GF, Gidding S, Wierzbicki AS, Toth PP, Alonso R, Brown WV, Bruckert E, Defesche J, Lin KK, Livingston M, Mata P, Parhofer KG, Raal FJ, Santos RD, Sijbrands EJ, Simpson WG, Sullivan DR, Susekov AV, Tomlinson B, Wiegman A, Yamashita S, Kastelein JJ. Integrated guidance on the care of familial hypercholesterolaemia from the International FH Foundation. Eur J Prev Cardiol. (2015) 22(7):849-54.

21. Wiegman A, Gidding SS, Watts GF, Chapman MJ, Ginsberg HN, Cuchel M, Ose L, Averna M, Boileau C, Borén J, Bruckert E, Catapano AL, Defesche JC, Descamps OS, Hegele RA, Hovingh GK, Humphries SE, Kovanen PT, Kuivenhoven JA, Masana L, Nordestgaard BG, Pajukanta P, Parhofer KG, Raal FJ, Ray KK, Santos RD, Stalenhoef AF, Steinhagen-Thiessen E, Stroes ES, Taskinen MR, Tybjærg-Hansen A, Wiklund O. Familial hypercholesterolaemia in children and adolescents: gaining decades of life by optimizing detection and treatment. Eur. (Heart) 36(1522-9645):2425-37.

22. Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, Braun LT, de Ferranti S, Faiella-Tommasino J, Forman DE, Goldberg R, Heidenreich PA, Hlatky MA, Jones DW, Lloyd-Jones D, Lopez-Pajares N, Ndumele CE, Orringer CE, Peralta CA, Saseen JJ, Smith SC, Sperling L, Virani SS, Yeboah J. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J. Am. Coll. (Cardiol)

23. Scottish Intercollegiate Guidelines Network. Risk estimation and the prevention of cardiovascular disease. (2017) Accessed: 2018-05-08. Website: http://www.sign.ac.uk/assets/sign1492.pdf

24. Vuorio A, Kuoppala J, Kovanen PT, Humphries SE, Tonstad S, Wiegman A, Drogari E, Ramaswami U. Statins for children with familial hypercholesterolemia. Cochrane Database Syst Rev. (2019) 2019(1469-493X).

25. Barkas F, Elisaf M, Milionis H. Statins decrease the risk of stroke in individuals with heterozygous familial hypercholesterolemia: A systematic review and meta-analysis. Atherosclerosis. (2015) 243(1):60-4.

26. Anderson TJ, Gregoire J, Pearson GJ, Barry AR, Couture P, Dawes M, Francis GA, Genest J Jr, Grover S, Gupta M, Hegele RA, Lau DC, Leiter LA, Lonn E, Mancini GB, McPherson R, Ngui D, Poirier P, Sievenpiper JL, Stone JA, Thanassoulis G, Ward R. 2016 Canadian Cardiovascular Society Guidelines for the Management of Dyslipidemia for the Prevention of Cardiovascular Disease in the Adult. Can J Cardiol. (2016) 32(11):1263-1282.

27. Ascaso JF, Civeira F, Guijarro C, López Miranda J, Masana L, Mostaza JM, Pedro-Botet J, Pintó X, Valdivielso P. Indications of PCSK9 inhibitors in clinical practice. Recommendations of the Spanish Sociey of Arteriosclerosis (SEA), 2019. (Clin) 31(1578-1879):128-139.

28. de Ferranti SD, Steinberger J, Ameduri R, Baker A, Gooding H, Kelly AS, Mietus-Snyder M, Mitsnefes MM, Peterson AL, St-Pierre J, Urbina EM, Zachariah JP, Zaidi AN. Cardiovascular Risk Reduction in High-Risk Pediatric Patients: A Scientific Statement From the American Heart Association. Circulation. (2019) 139(1524-4539):e603-e634.

29. Descamps OS, Van Caenegem O, Hermans MP, Balligand JL, Beauloye C, Bondue A, Carlier S, Castermans E, Chenot F, Claeys M, De Block C, de Leener A, De Meester A, Demeure F, De Raedt H, Desmet W, Elegeert I, Guillaume M, Hoffer E, Kacenelenbogen R, Lancellotti P, Langlois M, Leone A, Mertens A, Paquot N, Vanakker O, Vanoverschelde JL, Verhaegen A, Vermeersch P, Wallemacq C, Rietzschel E. A Belgian consensus strategy to identify familial hypercholesterolaemia in the coronary care unit and its subsequent cascade screening and treatment: BEL-FaHST (The BELgium Familial Hypercholesterolaemia STrategy). Atherosclerosis. (2018) 277(1879-1484):369-376.

30. Jacobson TA, Ito MK, Maki KC, Orringer CE, Bays HE, Jones PH, McKenney JM, Grundy SM, Gill EA, Wild RA, Wilson DP, Brown WV. National lipid association recommendations for patient-centered management of dyslipidemia: part 1--full report. Journal of clinical lipidology. (J) 9(1933-2874):129-69.

31. McDonagh M, Peterson K, Holzhammer B, Fazio S. A Systematic Review of PCSK9 Inhibitors Alirocumab and Evolocumab. J Manag Care Spec Pharm. (2016) 22(6):641-653q.

32. Thompson G, Parhofer KG. Current Role of Lipoprotein Apheresis. Curr Atheroscler Rep. (2019) 21(1534-6242):26.

33. Watts GF, Sullivan DR, Poplawski N, van Bockxmeer F, Hamilton-Craig I, Clifton PM, O'Brien R, Bishop W, George P, Barter PJ, Bates T, Burnett JR, Coakley J, Davidson P, Emery J, Martin A, Farid W, Freeman L, Geelhoed E, Juniper A, Kidd A, Kostner K, Krass I, Livingston M, Maxwell S, O'Leary P, Owaimrin A, Redgrave TG, Reid N, Southwell L, Suthers G, Tonkin A, Towler S, Trent R. Familial hypercholesterolaemia: a model of care for Australasia. Atheroscler Suppl. (2011) 12(1878-5050):221-63.

34. Harada-Shiba M, Arai H, Ishigaki Y, Ishibashi S, Okamura T, Ogura M, Dobashi K, Nohara A, Bujo H, Miyauchi K, Yamashita S, Yokote K. Guidelines for Diagnosis and Treatment of Familial Hypercholesterolemia 2017. J. Atheroscler. (Thromb)

35. Harada-Shiba M, Ohta T, Ohtake A, Ogura M, Dobashi K, Nohara A, Yamashita S, Yokote K. Guidance for Pediatric Familial Hypercholesterolemia 2017. J. Atheroscler. (Thromb)

36. Jacobson TA, Maki KC, Orringer CE, Jones PH, Kris-Etherton P, Sikand G, La Forge R, Daniels SR, Wilson DP, Morris PB, Wild RA, Grundy SM, Daviglus M, Ferdinand KC, Vijayaraghavan K, Deedwania PC, Aberg JA, Liao KP, McKenney JM, Ross JL, Braun LT, Ito MK, Bays HE, Brown WV, Underberg JA. National Lipid Association Recommendations for Patient-Centered Management of Dyslipidemia: Part 2. Journal of clinical lipidology. (J) 9(1933-2874):S1-122.

37. Kinoshita M, Yokote K, Arai H, Iida M, Ishigaki Y, Ishibashi S, Umemoto S, Egusa G, Ohmura H, Okamura T, Kihara S, Koba S, Saito I, Shoji T, Daida H, Tsukamoto K, Deguchi J, Dohi S, Dobashi K, Hamaguchi H, Hara M, Hiro T, Biro S, Fujioka Y, Maruyama C, Miyamoto Y, Murakami Y, Yokode M, Yoshida H, Rakugi H, Wakatsuki A, Yamashita S. Japan Atherosclerosis Society (JAS) Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2017. J. Atheroscler. (Thromb)

38. Robinson JG, Goldberg AC. Treatment of adults with familial hypercholesterolemia and evidence for treatment: recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin Lipidol. (2011) 5(1933-2874):S18-29.

39. The Royal Australian College of General Practitioners. Guidelines for preventive activities in general practice. 9th edn.. (2016) Accessed: 2018-05-08. Website: https://www.racgp.org.au/download/Documents/Guidelines/Redbook9/17048-Red-Book-9th-Edition.pdf

40. Abul-Husn NS, Manickam K, Jones LK, Wright EA, Hartzel DN, Gonzaga-Jauregui C, O'Dushlaine C, Leader JB, Lester Kirchner H, Lindbuchler DM, Barr ML, Giovanni MA, Ritchie MD, Overton JD, Reid JG, Metpally RP, Wardeh AH, Borecki IB, Yancopoulos GD, Baras A, Shuldiner AR, Gottesman O, Ledbetter DH, Carey DJ, Dewey FE, Murray MF. Genetic identification of familial hypercholesterolemia within a single U.S. health care system. Science. (2016) 354(6319).

41. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. HYPERCHOLESTEROLEMIA, FAMILIAL, 2; FCHL2. MIM: 144010: 2020 Jun 04. World Wide Web URL: http://omim.org.

42. Sjouke B, Kusters DM, Kindt I, Besseling J, Defesche JC, Sijbrands EJ, Roeters van Lennep JE, Stalenhoef AF, Wiegman A, de Graaf J, Fouchier SW, Kastelein JJ, Hovingh GK. Homozygous autosomal dominant hypercholesterolaemia in the Netherlands: prevalence, genotype-phenotype relationship, and clinical outcome. Eur Heart J. (2015) 36(9):560-5.

43. Baigent C, Blackwell L, Collins R, Emberson J, Godwin J, Peto R, Buring J, Hennekens C, Kearney P, Meade T, Patrono C, Roncaglioni MC, Zanchetti A. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet. (2009) 373(9678):1849-60.

44. National Institute for Health and Care Excellence. Ezetimibe for treating primary heterozygous-familial and non-familial hypercholesterolaemia. (2016) Accessed: 2018-05-08. Website: https://www.nice.org.uk/guidance/ta385

45. Rosenson RS, Baker SK, Jacobson TA, Kopecky SL, Parker BA, The National Lipid Association's Muscle Safety Expert Panel. An assessment by the Statin Muscle Safety Task Force: 2014 update. Journal of clinical lipidology. (J) 8(1933-2874):S58-71.