Familial hypercholesterolemia in children

INTRODUCTION — Familial hypercholesterolemia (FH) is a common autosomal codominant genetic disease. The clinical syndrome (phenotype) is characterized by:

●Elevated low-density lipoprotein cholesterol level from birth

●Xanthomata in untreated adults and children with homozygous FH (picture 1A-C)

●Increased risk of premature atherosclerotic cardiovascular disease (ASCVD)

The diagnosis and management of FH presenting during childhood will be reviewed here. A broader discussion of pediatric lipid disorders, including our approach to screening for FH and other pediatric dyslipidemias, is provided in a separate topic review. (See "Dyslipidemia in children and adolescents: Definition, screening, and diagnosis" and "Dyslipidemia in children and adolescents: Management".)

The diagnosis, evaluation, and treatment of FH in adults are also discussed separately. (See "Familial hypercholesterolemia in adults: Overview" and "Familial hypercholesterolemia in adults: Treatment".)

PREVALENCE — Reported prevalence rates of FH vary depending on the definition used and the population studied. Heterozygous FH (HeFH) is estimated to occur in approximately 1 in 200 to 300 individuals [1-4]. In contrast, homozygous FH (HoFH) is rare with an estimated prevalence of approximately 1:300,000 to 1:400,000 [5]. The prevalence of FH is discussed in greater detail separately. (See "Familial hypercholesterolemia in adults: Overview", section on 'Prevalence'.)

GENETICS — FH is most commonly caused by mutations in the low-density lipoprotein receptor gene (LDLR). The phenotype of FH can also be seen with mutations in the genes that code for proprotein convertase subtilisin kexin 9 (PCSK9) and apolipoprotein B (APOB). Individuals with phenotypic FH who do not have mutations in one of these key causative mutations may have polygenetic defects. FH is inherited with a gene dosing effect, in which homozygotes are more adversely affected than heterozygotes (figure 1). The genetics of FH are discussed in greater detail separately. (See "Familial hypercholesterolemia in adults: Overview", section on 'Genetic considerations'.)

SCREENING — The first step in FH screening is usually a lipid profile. In fact, an important goal of lipid screening in childhood and adolescence is to identify and treat individuals with FH, a group at high risk for morbidity and early mortality.

●Universal screening – Universal lipid screening is suggested twice during childhood/adolescence (once between the age of 9 and 11 years and again between age 17 and 21 years) to identify FH. Earlier and more frequent lipid screening is appropriate for children with a family history of premature atherosclerotic cardiovascular disease (ASCVD) or high cholesterol. The approach to lipid screening in children and adolescents is summarized in the algorithms and is discussed in greater detail separately (algorithm 1A-B). (See "Dyslipidemia in children and adolescents: Definition, screening, and diagnosis", section on 'Approach to screening'.)

●Cascade screening – Children with a family history of premature ASCVD or very high cholesterol should be tested for FH as early as age two years. Identification of one family member with FH, either by lipid values or by molecular diagnosis, should prompt screening of other first- and second-degree relatives (eg, cascade screening). (See 'Testing family members' below.)

EVALUATION

Clinical suspicion — A diagnosis of FH should be suspected in the following settings [1,6,7]:

●Elevated plasma low-density lipoprotein cholesterol (LDL-C) in the child – The level of LDL-C that warrants further evaluation depends upon whether additional family members have known hypercholesterolemia or premature atherosclerotic cardiovascular disease (ASCVD):

•In patients with a negative or unknown family history, an LDL-C level of ≥190 mg/dL (4.9 mmol/L) suggests FH

•In patients with a positive family history of hypercholesterolemia and/or premature ASCVD, an LDL-C level of ≥160 mg/dL (4.1 mmol/L) is suggestive of FH.

●Elevated plasma LDL-C or known FH in family members (total cholesterol [TC] >240 mg/dL [6.2 mmol/L] in either parent).

●Tendon xanthomas in the child or family member(s).

●Premature ASCVD in the child or family member(s) – Premature ASCVD is generally defined as any of the following before age 55 years in males or before age 65 years in females:

•Heart attack

•Treated angina

•Interventions for coronary artery disease (CAD)

•Sudden cardiac death

•Ischemic stroke

Evaluation — Evaluation of a child or adolescent with suspected FH includes the following:

Family history — A detailed family history is essential in establishing the diagnosis of FH. Identifying family members with premature ASCVD, tendon xanthomas, and elevated cholesterol levels (particularly if present during childhood) helps support the diagnosis of FH. The historian should ask about siblings, parents, aunts, uncles, and grandparents; information about more distant relatives may also be informative.

Physical examination — The physical examination is directed at identifying abnormal deposits of cholesterol in the skin and eyes. These are rarely seen in children except in individuals with homozygous FH and certain other rare genetic conditions (eg, sitosterolemia, cerebrotendinous xanthomatosis) (see 'Differential diagnosis' below):

●Tendon xanthomata (picture 1A-C) are most common in the Achilles tendons and dorsum of the hands but can occur at other sites. Tendon xanthomata in children are highly suggestive of homozygous FH (HoFH).

●Tuberous xanthomata (picture 2A-B) typically occur over extensor surfaces such as the knee and elbow.

●Planar xanthomas (picture 3) may occur on the palms of the hands and soles of the feet and are often painful.

●Xanthelasmas (picture 4) are cholesterol-filled, soft, yellow plaques that usually appear on the medial aspects of the eyelids.

●Corneal arcus (picture 5) is a white or grey ring around the cornea.

Lipid profile — The characteristic fasting lipid profile in patients with FH consists of (see 'Clinical suspicion' above):

●Elevated TC

●Elevated LDL-C

●Normal or low high-density lipoprotein cholesterol (HDL-C)

●Normal triglyceride (TG) levels unless the child is obese, in which case TG levels may be elevated. Elevated TG levels do not exclude the diagnosis of FH; however, other potential causes of hypertriglyceridemia should be considered.

Evaluate for secondary causes — An evaluation for secondary causes of hypercholesterolemia (table 1) should be performed as described separately. (See "Dyslipidemia in children and adolescents: Definition, screening, and diagnosis", section on 'Secondary causes of hypercholesterolemia'.)

Genetic testing — Testing for mutations in the LDLR, APOB, and PCSK9 genes should be offered to pediatric patients with xanthomata or a clinical picture of HoFH based on the criteria discussed below [1]. (See 'Homozygous FH (HoFH)' below.)

The benefits of genetic testing in children whose clinical picture is consistent with heterozygous FH (HeFH) is less clear and its role in the diagnosis and treatment of this population is evolving. Potential benefits of genetic testing in HeFH include improved adherence to recommended therapy, impact on cascade screening of relatives, and counseling the parents about future pregnancies. In addition, genetic testing provides clarity in the diagnosis, which may guide management decisions, particularly regarding use of statin therapy for individuals with borderline LDL-C levels.

Genetic testing should be performed in consultation with a lipid specialist and/or geneticist.

DIAGNOSIS

Heterozygous FH (HeFH) — The diagnosis of HeFH can be made clinically and through molecular genetic testing.

●Clinical diagnosis – The clinical diagnosis of heterozygous FH is generally based on [8]:

•High levels of total and LDL-C, plus one or more of the following:

-Family history of hypercholesterolemia (especially in children) or known FH

-History of premature ASCVD in the patient or in family members

-Physical examination findings of abnormal deposition of cholesterol in extravascular tissues (eg, tendon xanthoma (picture 1A-B)), although these rarely occur in childhood

Different definitions of FH are used in different parts of the world, and there is some variation in diagnostic criteria:

•The American Heart Association (AHA) criteria [8]:

-LDL-C ≥155 mg/dL (4 mmol/L), plus

-Positive family history of elevated LDL-C or premature ASCVD, plus

-Exclusion of secondary causes of hypercholesterolemia

•Simon Broome Register Group (table 2) [9]

•Dutch Lipid Clinic Network (DLCN) criteria, applicable to adult patients (table 3) [1]

In our practice, we typically use the AHA criteria. Simon Broome criteria are used predominately in the United Kingdom. The DLCN criteria do not include pediatric criteria and are not applicable in childhood.

●Molecular diagnosis – A definitive diagnosis of heterozygous FH can be made by identifying a causative mutation in the, and genes. However, genetic testing is not required to establish the diagnosis. (See 'Genetic testing' above.)

Homozygous FH (HoFH) — Genetic testing should be performed in individuals with suspected homozygous FH.

●Clinical suspicion – Homozygous FH should be suspected in individuals who meet the following criteria [10]:

•Untreated LDL-C >500 mg/dL (>13 mmol/L) or treated LDL-C ≥300 mg/dL (>8 mmol/L), plus either of the following:

-Cutaneous or tendon xanthoma (picture 1A-B) before age 10 years, or

-Elevated LDL-C levels consistent with heterozygous FH in both parents

It is important to note that untreated LDL-C levels <500 mg/dL (12.9 mmol/L) may be seen in some individuals with homozygous FH, particularly in very young children, and genetic testing should be considered to make the diagnosis of homozygous FH.

●Molecular diagnosis – The definitive diagnosis of homozygous FH is established by identifying causative mutation(s) in the LDLR, APOB, and PCSK9 genes.

Testing family members — Once FH is diagnosed, either by clinically or with molecular testing, it is appropriate to test other family members to see if they are affected. This is referred to as "cascade screening." Testing is performed in first- and second-degree relatives (eg, siblings, parents, grandparents, aunts, and uncles). Testing can be accomplished using a fasting lipid profile or a nonfasting TC and HDL-C. If molecular diagnosis has been made, targeted genetic testing for the specific defect is appropriate, along with a lipid profile to assess the need for lipid lowering treatment.

DIFFERENTIAL DIAGNOSIS — It is important to distinguish FH from other causes of hypercholesterolemia, xanthomata, and/or premature atherosclerotic cardiovascular disease (ASCVD):

●Hypercholesterolemia and premature ASCVD – Other causes of hypercholesterolemia and premature ASCVD include (table 4):

•Familial combined hyperlipidemia (see "Inherited disorders of LDL-cholesterol metabolism other than familial hypercholesterolemia", section on 'Familial combined hyperlipidemia')

•Familial hyperapobetalipoproteinemia (likely a variant of familial combined hyperlipidemia)

•Polygenic hypercholesterolemia (see "Inherited disorders of LDL-cholesterol metabolism other than familial hypercholesterolemia", section on 'Polygenic hypercholesterolemia')

•Familial dysbetalipoproteinemia (type III hyperlipoproteinemia) (see "Hypertriglyceridemia in adults: Approach to evaluation", section on 'Etiology')

•Secondary causes of dyslipidemia (table 1) and premature atherosclerosis (see "Overview of risk factors for development of atherosclerosis and early cardiovascular disease in childhood")

The clinical history and evaluation of the lipid profile are helpful in distinguishing these disorders.

●Xanthomata – Xanthomata in children are highly suggestive of homozygous FH, but they can be seen on other rare genetic disorders such as sitosterolemia and cerebrotendinous xanthomatosis, described below. In addition, juvenile xanthogranulomas (JXG) (picture 6A-B) and other non-Langerhans cell histiocytoses have a similar appearance and may be mistaken for xanthomata. The distribution of the lesions helps to differentiate xanthomata in FH from the lesions in JXG (in FH, xanthomata commonly occur on Achilles tendons, dorsum of the hands, and extensor surfaces of the knees and elbows, whereas lesions in JXG typically occur on the head, neck, and upper trunk). A definitive distinction is made on the basis of the lipid profile, which is normal in JXG. (See "Juvenile xanthogranuloma (JXG)".)

●Tendon xanthomata and premature atherosclerosis – Tendon xanthomata and premature atherosclerosis can also occur in several rare genetic disorders:

•Sitosterolemia – Sitosterolemia (alternatively termed "phytosterolemia") is an autosomal recessive disorder associated with hyperabsorption of cholesterol and plant sterols from the intestine [11]. It is characterized by tendinous and/or tuberous xanthomas in childhood associated with high plasma cholesterol and atherosclerotic complications. Sitosterolemia can be differentiated from FH based upon markedly (>30-fold) increased plasma concentrations of plant sterols. In addition, patients with sitosterolemia typically respond well to diet restricting plant-based mono and polyunsaturated fats, bile acid sequestrants, and ezetimibe, which generally is not the case in patients with homozygous FH. Diagnosis of sitosterolemia is confirmed by genetic analysis, with detection of mutations in two adenosine triphosphate -binding cassette transporter (ABC transporters) genes, ABCG5, and/or ABCG8 [10].

•Cerebrotendinous xanthomatosis – Cerebrotendinous xanthomatosis is caused by a block in bile acid synthesis due to the absence of hepatic mitochondrial 27-hydroxylase (CYP27A1). It can be distinguished from FH by the presence of neurologic, cognitive, and ophthalmic symptoms and usually normal serum cholesterol concentrations. (See "Cerebrotendinous xanthomatosis".)

•Lysosomal acid lipase deficiency – Lysosomal acid lipase deficiency (also called cholesterol ester storage disease) is an autosomal recessive disorder in which low-density lipoprotein cholesterol levels are elevated (typically in the range of 200 to 300 mg/dL) with low high-density lipoprotein cholesterol levels and elevated triglycerides [12]. Additional characteristic findings in affected children may include hepatosplenomegaly and elevated liver enzymes. Xanthomata and premature atherosclerosis can occur, but these findings are generally not seen until adulthood. The diagnosis is confirmed with molecular testing and enzyme activity assays. (See "Metabolic dysfunction-associated steatotic liver disease in children and adolescents".)

MANAGEMENT

Management of HeFH — Children and adolescents with heterozygous FH (HeFH) have an increased risk of premature atherosclerotic cardiovascular disease (ASCVD). They should generally be referred to a pediatric lipid specialist (if available) and treated aggressively [6,13]. A pediatric lipid specialist is typically pediatric cardiologist (or an endocrinologist, gastroenterologist, or general pediatrician), who has completed additional training in lipid disorders through a senior fellowship or via professional societies. If a pediatric lipid specialist is not available locally, referral to an adult lipid specialist may be helpful, particularly for adolescents.

The practice presented in the following sections is generally consistent with the 2019 American Heart Association (AHA) scientific statement on cardiovascular risk reduction in high-risk pediatric patients, the 2018 American College of Cardiology/AHA cholesterol guidelines, and the 2014 European Atherosclerosis Society FH guidelines [10,13,14]. Links to these and other society guidelines are provided separately. (See 'Society guideline links' below.)

Additional details regarding statins and other lipid lowering therapies in children are provided separately. (See "Dyslipidemia in children and adolescents: Management", section on 'Statin therapy' and "Dyslipidemia in children and adolescents: Management", section on 'Second-line agents and other therapies'.)

Treatment goals — The management approach in children with HeFH is generally similar to the management of other causes of pediatric hypercholesterolemia, which is summarized in the algorithms (algorithm 2A-B) and discussed in detail separately. (See "Dyslipidemia in children and adolescents: Management", section on 'Hypercholesterolemia'.)

For children and adolescents with HeFH, a combination of lifestyle and medical management is generally required to sufficiently lower LDL-C. The goal of treatment is to reduce LDL-C minimally to a level <130 mg/dL (3.4 mmol/L) and ideally below 100 mg/dL (2.6 mmol/L). This usually represent a 50 percent reduction (approximately) from pretreatment levels.

Key distinctions between HeFH and other types of dyslipidemia — Although the management approach for children with HeFH is generally similar to the general approach, there are some key distinctions in children with HeFH:

●Children with HeFH are unlikely to respond sufficiently to dietary modification alone and therefore they are likely to require statin therapy. (See "Dyslipidemia in children and adolescents: Management", section on 'Statin therapy'.)

●Children with HeFH may benefit from statin therapy at an earlier age (as early as age eight depending on low-density lipoprotein cholesterol [LDL-C] levels and family history of ASCVD).

●Children with HeFH are more likely to require a second lipid-lowering agent in addition to statin therapy, although high-intensity statin at moderate to high doses is often sufficient. In our practice, when a second agent is required, we typically initiate ezetimibe for the reasons discussed separately. (See "Dyslipidemia in children and adolescents: Management", section on 'Second-line agents and other therapies'.)

●Children with HeFH are likely to have affected family members. Thus, testing should be offered to first- and second-degree relatives of individuals with FH. (See 'Testing family members' above.)

Timing for initiating treatment — The optimal age at which to initiate treatment of children with HeFH is unknown. Many clinicians begin therapy at age 10 years based upon prospective studies suggesting that differences in preclinical markers of atherosclerosis (eg, carotid intima-media thickness [CIMT]) between children with HeFH and their unaffected siblings are detectable starting at approximately age 10 years of age [15,16]. If the LDL-C elevations are severe, the family history is particularly concerning, and lifestyle modification is not effective, treatment can be started before age 10 years under the care of a pediatric lipid specialist.

Benefits of statin therapy — Clinical trials and meta-analyses of randomized trials have found that statin therapy in children with HeFH reduces LDL-C levels by approximately 25 to 40 percent, depending on dose and potency [17-19]. In the available trials, rates of adverse effects (ie, hepatic and muscular toxicity) in children treated with statins were similar to those treated with placebo, and no effects on sexual development were seen [18,19]. No serious adverse events were reported in one study with 20-year follow-up, though 2 percent stopped taking the drug due to adverse side effects [20].

Some studies have also demonstrated improvements in preclinical markers of atherosclerosis, including CIMT and flow-mediated dilation (FMD), a measure of endothelial function [15,17,21-23].

The most compelling evidence for the benefits of statin therapy in children with FH comes from a clinical trial in which 214 children with HeFH were randomly assigned to treatment with a statin (pravastatin) or placebo [21]. The initial trial ran for two years, after which most patients in the placebo arm were switched to a statin. The children enrolled in the trial and their unaffected siblings were then followed for 20 years to assess the long-term effects of statin therapy [15,20,22]. In the original trial, pravastatin reduced LDL-C by 24 percent and children treated with a pravastatin had regression in CIMT, while patients treated with placebo demonstrated the expected progression of increased CIMT [21]. Two follow-up reports suggested that earlier intervention delayed progression of preclinical atherosclerosis and slowed the rate of CIMT progression to levels comparable with those of their unaffected siblings [15,22]. In a report of 20-year follow-up of 184 patients enrolled in the original trial and 77 of their unaffected siblings, the benefits of starting statin therapy in childhood on lowering LDL-C and slowing progression of CIMT persisted into adulthood such that the rate of CIMT progression was identical to that of unaffected siblings [20]. To assess whether early initiation of statin therapy in childhood was associated with a lower rate of cardiovascular events in adulthood, the investigators compared cardiovascular outcomes in the trial participants (n = 203) with outcomes of their parents who were also affected by HeFH (n = 156) but for whom statins were only available much later in life. Trial participants had considerably fewer cardiovascular events by age 40 years compared with their affected parents (1 versus 26 percent).

Other clinical trials have also demonstrated medium-term benefits in reducing subclinical vascular changes in children with FH [17,23].

Other agents

●Ezetimibe – Studies in adolescents and adults with HeFH have demonstrated that the combination of a statin plus ezetimibe lowers LDL-C to a greater extent than monotherapy with statin [24,25]. In a study of 248 male and female adolescents with HeFH, combination ezetimibe-simvastatin reduced LDL-C by an additional 15 percent and was not associated with increased risk of adverse events compared with a similar dose of simvastatin monotherapy during up to 53 weeks of therapy [25]. (See "Dyslipidemia in children and adolescents: Management", section on 'Second-line agents and other therapies'.)

●PCSK9 inhibitors – Use of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors (eg, evolocumab and alirocumab) is generally limited to patients with persistently elevated LDL-C despite treatment with maximal statin therapy and those who cannot tolerate maximal statin therapy. In the United States, evolocumab is approved for use in patients aged ≥10 years with HeFH or HoFH [26]; alirocumab is approved only for use in adult patients. In Europe, evolocumab is approved for use in patients ≥12 years old with homozygous FH [27]. In a randomized trial involving 157 adolescent patients with HeFH, evolocumab reduced LDL-C levels by approximately 40 percent relative to placebo [28]. (See "PCSK9 inhibitors: Pharmacology, adverse effects, and use".)

Management of HoFH — Children with clinically suspected homozygous FH (HoFH) based on phenotype (ie, untreated LDL-C ≥500 mg/dL [12.9 mmol/L]) or confirmed HoFH by genetic testing, should be managed by a pediatric lipid specialist and a pediatric cardiologist.

Comprehensive cardiovascular evaluation — Children with HoFH should undergo a comprehensive cardiovascular evaluation at diagnosis and at periodic follow-up. Testing includes:

●Electrocardiogram.

●Echocardiography to evaluate for supravalvar aortic stenosis and for left ventricular dysfunction including segmental wall motion abnormalities.

●Functional testing (ie, exercise stress testing, including stress echocardiography looking for segmental wall motion abnormalities and function augmentation) if child is old enough to cooperate with such testing.

●Coronary artery imaging – In our practice, we perform coronary angiography at the time of diagnosis to establish the child's baseline and to guide the intensity of lipid lowering therapies. Angiography is then performed every two to three years depending on the degree of lipid lowering and index of suspicion with regard to clinically manifest atherosclerosis. A low threshold for evaluation is warranted since signs and symptoms of myocardial ischemia in children are often "atypical" (eg, nausea, vomiting, pallor, sweating, throat pain, and ear pain with or without accompanying chest pain). Coronary angiography can be performed invasively via cardiac catheterization or noninvasively with computed tomography (CT). CT angiography is a useful alternative to invasive angiography because of its ability to demonstrate atherosclerotic plaque beyond coronary lumen dimensions [29].

Management principles — Children and adolescents with HoFH should receive prompt and aggressive lipid-lowering therapy beginning at the time of diagnosis [8,10,13].

Management is carried out in a stepwise fashion targeting a goal LDL-C value of <135 mg/dL (3.5 mmol/L) [10]:

●High potency statin therapy should be initiated along with lifestyle advice at the time of diagnosis, even in infancy. (See "Dyslipidemia in children and adolescents: Management", section on 'Dietary modification' and "Dyslipidemia in children and adolescents: Management", section on 'Statin therapy'.)

●Most patients with HoFH only achieve modest reductions in LDL-C levels with diet and statin therapy, even at maximal doses. Ezetimibe is initiated as an additional treatment early on. Bile acid sequestrants or nicotinic acid are alternatives, but compliance with these agents is often poor. (See "Dyslipidemia in children and adolescents: Management", section on 'Second-line agents and other therapies'.)

●Additional treatments are invariably required. These include anti-PCSK9 therapy, evinacumab, LDL apheresis, and lomitapide. Use of anti-PCSK9 therapy depends in part on the genetic diagnosis; it is generally not effective for patients with null LDL-R defects. Evinacumab, an antibody therapy directed against ANGPTL3, lowers LDL independent of the LDL receptor, making it an effective therapy in those with null defects [30-32]. Liver transplant has been described as a last resort intervention, though this is rarely necessary in the modern era with the availability of newer lipid-lowering drugs [33]. In our experience, most patients with homozygous FH achieve adequate lipid lowering with a combination of statin, ezetimibe, LDL apheresis, PCSK9 inhibitors (if there is any LDL receptor function), evinacumab, and lomitapide. (See "Dyslipidemia in children and adolescents: Management", section on 'Second-line agents and other therapies' and "Treatment of drug-resistant hypercholesterolemia".)

●In addition to lipid-lowering therapy, low-dose aspirin and beta blocker therapy are appropriate for children with established atherosclerotic coronary artery disease (CAD) based on the established benefits of these drugs in adults with CAD. (See "Aspirin for the secondary prevention of atherosclerotic cardiovascular disease" and "Beta blockers in the management of chronic coronary syndrome".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Lipid disorders and atherosclerosis in children".)

SUMMARY AND RECOMMENDATIONS

●Definition – Familial hypercholesterolemia (FH) is a common autosomal codominant genetic disease. The clinical syndrome (phenotype) is characterized by (see 'Introduction' above):

•Elevated low-density lipoprotein cholesterol (LDL-C) level from birth.

•Xanthomata in untreated adults and younger individuals with homozygous FH (picture 1A-C).

•Increased risk of premature atherosclerotic cardiovascular disease (ASCVD).

●Genetics – FH is inherited with a gene-dosing effect, in which homozygotes are more adversely affected than heterozygotes (figure 1). Homozygotes generally manifest coronary artery disease (CAD) in childhood; untreated homozygous FH (HoFH) is life threatening. (See 'Genetics' above.)

●Prevalence – Heterozygous FH (HeFH) is estimated to occur in approximately 1 in 200 to 300 individuals. In contrast, HoFH is rare, with an estimated prevalence of approximately 1:300,000 to 1:400,000. (See 'Prevalence' above and "Familial hypercholesterolemia in adults: Overview", section on 'Prevalence'.)

●Screening – Selective, cascade, and universal lipid screening during childhood and adolescence play key roles in identifying and treating individuals with FH. The suggested approach to lipid screening in childhood and adolescence is summarized in the algorithms and is discussed in greater detail separately (algorithm 1A-B). (See "Dyslipidemia in children and adolescents: Definition, screening, and diagnosis", section on 'Rationale for lipid screening'.)

●Clinical suspicion – FH should be suspected in the following settings (see 'Clinical suspicion' above):

•High cholesterol in the child

•High cholesterol or known FH in family members

•Tendon xanthomata in the child or in family members

•Premature ASCVD in the child or in family members

●Evaluation – Evaluation for FH includes (see 'Evaluation' above):

•Detailed family history. (See 'Family history' above.)

•Physical examination, which in severe cases may show abnormal deposits of cholesterol (eg, tendon xanthomata (picture 1A-C), tuberous xanthomata (picture 2A-B), xanthelasmas (picture 4), corneal arcus (picture 5)). (See 'Physical examination' above.)

•Fasting lipid profile (typical pattern is elevated total cholesterol and LDL-C, with normal or low high-density lipoprotein cholesterol and normal triglycerides). (See 'Lipid profile' above.)

•Evaluation to exclude secondary causes of elevated LDL-C (table 1). (See "Dyslipidemia in children and adolescents: Definition, screening, and diagnosis", section on 'Secondary causes of hypercholesterolemia'.)

•Genetic testing should be offered to children who have findings consistent with HoFH (ie, xanthomata and/or LDL-C levels >500 mg/dL [>13 mmol/L]). The role of genetic testing in individuals with suspected HeFH is less clear. (See 'Genetic testing' above.)

●Diagnosis – The diagnosis of FH can be made clinically and/or with molecular genetic testing (see 'Diagnosis' above):

•HeFH – The clinical diagnosis of HeFH is based on high cholesterol levels in combination with family history of hypercholesterolemia, family or personal history of premature atherosclerotic CVD, and/or physical examination findings of xanthomata (although these rarely occur in childhood). The clinical criteria differ somewhat depending on the specific clinical definition used. Commonly used definitions include the American Heart Association (AHA) criteria, the Simon Broome Register Group (table 2), and the Dutch Lipid Clinic Network criteria for adults (table 3). (See 'Heterozygous FH (HeFH)' above.)

•HoFH – HoFH should be suspected in patients with markedly elevated cholesterol levels (ie, untreated LDL-C >500 mg/dL [>13 mmol/L] or treated LDL-C ≥300 mg/dL [>8 mmol/L]) in combination with cutaneous or tendon xanthoma before age 10 years and/or elevated cholesterol levels in both parents. A definitive diagnosis is made by identifying causative mutations in the LDL receptor (LDLR), apolipoprotein B (APOB), or proprotein convertase subtilisin/kexin type 9 (PCSK9) genes. (See 'Homozygous FH (HoFH)' above.)

●Differential diagnosis – FH can be distinguished from other causes of hypercholesterolemia, xanthomata, and premature atherosclerotic CVD on the basis of the family and clinical history, physical examination, lipid profile, and genetic testing (table 4). (See 'Differential diagnosis' above.)

●Management

•HeFH – For children and adolescents with HeFH, a combination of lifestyle and medical management is generally required to sufficiently lower LDL-C. The goal of treatment is to reduce LDL-C minimally to a level <130 mg/dL (3.4 mmol/L) and ideally <100 mg/dL (2.6 mmol/L). (See 'Treatment goals' above.)

The initial management approach for pediatric patients with HeFH is generally similar to the management of other causes of pediatric hypercholesterolemia, though there are some distinctions as outlined above. (See 'Key distinctions between HeFH and other types of dyslipidemia' above.)

The management approach is summarized in the algorithms (algorithm 2A-B) and discussed in detail separately. (See "Dyslipidemia in children and adolescents: Management", section on 'Hypercholesterolemia'.)

•HoFH – Children with HoFH should be managed by a pediatric lipid specialist and a pediatric cardiologist. Management includes (see 'Management of HoFH' above):

-Comprehensive cardiovascular evaluation – The evaluation at initial diagnosis and at periodic follow-up includes electrocardiogram, echocardiography, stress testing (if the child is old enough to cooperate), and coronary angiography by computed tomography or cardiac catheterization.

-Prompt and aggressive lipid-lowering therapy – Management is carried out in a stepwise fashion targeting a goal LDL-C value of <135 mg/dL (3.5 mmol/L). For all individuals with HoFH, we recommend initiating high-potency statin therapy in addition to lifestyle advice at the time of diagnosis (Grade 1B). For most patients, we suggest adding ezetimibe as the second lipid-lowering agent (Grade 2B). Additional treatments are invariably required. These include anti-PCSK9 therapy (if there is any LDL receptor function), LDL apheresis, evinacumab, and lomitapide. (See "Dyslipidemia in children and adolescents: Management", section on 'Second-line agents and other therapies' and "Treatment of drug-resistant hypercholesterolemia".)

-Appropriate medical management of CAD – For children with clinically significant CAD, we suggest treatment with low-dose aspirin and beta blocker therapy (Grade 2B). This is based on the established benefits of these drugs in adults with CAD. (See "Aspirin for the secondary prevention of atherosclerotic cardiovascular disease" and "Beta blockers in the management of chronic coronary syndrome".)