Clinical characteristics.

Familial hypercholesterolemia (FH) is characterized by severely elevated LDL cholesterol (LDL-C) levels that lead to atherosclerotic plaque deposition in the coronary arteries and proximal aorta at an early age, leading to an increased risk for cardiovascular disease. Xanthomas (patches of yellowish cholesterol buildup) may worsen with age as a result of extremely high cholesterol levels. Xanthomas can occur around the eyelids and within the tendons of the elbows, hands, knees, and feet. In FH, the more common cardiovascular disease is coronary artery disease (CAD), which may manifest as angina and myocardial infarction; stroke occurs more rarely. Untreated men are at a 50% risk for a fatal or non-fatal coronary event by age 50 years; untreated women are at a 30% risk by age 60 years.

An estimated 70%-95% of FH results from a heterozygous pathogenic variant in one of three genes (APOB, LDLR, PCSK9). FH is the most common inherited cardiovascular disease, with a prevalence of 1:200-250. FH likely accounts for 2%-3% of myocardial infarctions in individuals younger than age 60 years.

In contrast, homozygous FH (HoFH) results from biallelic (homozygous or compound heterozygous) pathogenic variants in one of these known genes (APOB, LDLR, PCSK9). Most individuals with HoFH experience severe CAD by their mid-20s and the rate of either death or coronary bypass surgery by the teenage years is high. Severe aortic stenosis is also common.

Diagnosis/testing.

Several formal diagnostic criteria exist for FH. The diagnostic criteria most widely used in Western countries include: extreme hypercholesterolemia (untreated adults with LDL-C>190 mg/dL or total cholesterol levels >310 mg/dL; untreated children/adolescents with LDL-C levels >160 mg/dL or total cholesterol levels >230 mg/dL); history of premature CAD or other CVD; xanthomas; corneal arcus; and a family history of features suggestive of FH. The diagnosis of FH can also be established by identification of a heterozygous pathogenic variant in one of the three genes (APOB, LDLR, and PCSK9) known to be associated with FH.

The diagnosis of HoFH can be established in a proband by identification of biallelic pathogenic variants in one of the three genes (APOB, LDLR, and PCSK9) known to be associated with FH.

Management.

Treatment of manifestations: Adults with FH: reduce CAD risk factors including cessation of smoking, regular physical activity, healthy diet and weight control; treatment of hypertension; low-dose aspirin in high-risk individuals; pharmacotherapy (statins with additional medications as needed) to reduce lipid levels; referral to a lipid specialist if necessary to reduce LDL-C levels. Children with FH: referral to a lipid specialist; diet and lifestyle modifications; statins can be used in children starting around age eight years. Children and adults with HoFH: referral to a lipid specialist or specialized center for management of multiple drug therapy; LDL apheresis is often required; liver transplantation in rare circumstances.

Prevention of primary manifestations: Statin-based therapy with addition of other medications as needed, in combination with a heart-healthy diet (including reduced intake of saturated fat and increased intake of soluble fiber to 10-20 g/day); increased physical activity; not smoking.

Surveillance: Children with an established diagnosis of FH or risk factors for FH (e.g., elevated serum cholesterol, a family history of FH, a family history of premature CAD or other CVD) should have lipid levels checked before age ten years. All individuals with FH should have lipid levels monitored as recommended. Individuals with HoFH should be monitored with various imaging modalities (including echocardiograms, CT angiograms and cardiac catheterization) as recommended.

Agents/circumstances to avoid: Smoking, high intake of saturated and trans unsaturated fat, excessive intake of cholesterol, sedentary lifestyle, obesity, hypertension, and diabetes mellitus.

Evaluation of relatives at risk: Early diagnosis and treatment of first-degree and second-degree relatives at risk for FH can reduce morbidity and mortality. The genetic status of at-risk family members can be clarified by either: (1) molecular genetic testing if the pathogenic variant has been identified in an affected family member; or (2) measurement of LDL-C concentration.

Pregnancy management: Pregnant women should incorporate all the recommended lifestyle changes including low-saturated fat intake, no smoking, and high dietary soluble fiber. Statins are contraindicated in pregnancy due to concerns for teratogenicity and should be discontinued prior to conception. Bile acid binding resins (e.g., colesevelam) are generally considered safe (Class B for pregnancy), and LDL apheresis is also occasionally used if there is evidence of established CAD.

Genetic counseling.

Heterozygous familial hypercholesterolemia (FH) and homozygous familial hypercholesterolemia (HoFH) are inherited in an autosomal dominant manner.

Almost all individuals diagnosed with FH have an affected parent; the proportion of FH caused by a de novo pathogenic variant is unknown but appears to be extremely low. Each child of an individual with FH has a 50% chance of inheriting the pathogenic variant.

If both parents have FH, each child has a 50% chance of having FH, a 25% chance of having HoFH, and a 25% chance of not having FH.

If the pathogenic variant has been identified in a family member with FH (or if both pathogenic variants have been identified in a family member with HoFH), prenatal testing for pregnancies at increased risk is possible.

Suggestive Findings

Familial hypercholesterolemia (FH) should be suspected in individuals with the following findings

• Extreme hypercholesterolemia
  • Adults (untreated):
    • Low-density lipoprotein cholesterol (LDL-C) levels >190 mg/dL (>4.9 mmol/L)
    • Total cholesterol levels >310 mg/dL (>8 mmol/L)
  • Children/adolescents (untreated):
    • LDL-C levels >130 mg/dL (>3.4 mmol/L)
    • Total cholesterol levels >230 mg/dL (>6 mmol/L)
• History of premature coronary artery disease (CAD) or other cardiovascular disease (CVD) (e.g., angina pectoris, myocardial infarction, peripheral vascular disease)
• Physical examination findings (e.g., xanthomas, corneal arcus)
• Family history of premature CAD and/or CVD

Establishing the Diagnosis

Currently three formal diagnostic criteria for FH are widely used in Western countries. (See Harada-Shiba et al [2012] for criteria used in non-Western countries.)

• US MEDPED Program
• UK Simon Broome Familial Hypercholesterolæmia Registry
• Dutch Lipid Clinic Network

All three criteria rely on a combination of the following:

• Extreme hypercholesterolemia
• History of premature CAD or other CVD
• Findings on physical examination
• Family history of premature CAD or other CVD
• Identification of a pathogenic variant in a gene known to be associated with FH (see Table 1)

Extreme hypercholesterolemia

• Adults (untreated):
  • LDL-C levels >190 mg/dL (>4.9 mmol/L)
  • Total cholesterol levels >310 mg/dL (>8 mmol/L)
• Children or adolescents (untreated):
  • LDL-C levels >160 mg/dL (>4 mmol/L)
  • Total cholesterol levels >230 mg/dL (>6 mmol/L)

Note: (1) A non-fasting lipid panel can be obtained first in the initial evaluation of children, and, if abnormal or borderline, a fasting LDL-C level should be obtained [Martin et al 2013]. Elevation of two consecutive LDL-C levels is often recommended to confirm the diagnosis. (2) Age-specific LDL-C or total cholesterol levels are more specific in determining the likelihood of FH; for instance, LDL-C or total cholesterol levels >95th percentile for age, gender, and country [Starr et al 2008, Nordestgaard et al 2013]. (3) Computer (including mobile or smart phone-based) applications (see FH Diagnosis) can assist with the determination of the likelihood of FH based on the formal diagnostic criteria.

History of premature CAD or other CVD

• Angina pectoris
• Myocardial infarction
• Peripheral vascular diseases

Note: Although stroke is possible, it is less common in FH than premature CAD [Huxley et al 2003].

Physical examination findings

• Xanthomas (patches of yellowish cholesterol buildup). Common locations include around the eyelids, tendons of the elbows, hands, knees, and feet, particularly the Achilles tendon. Interdigital xanthomas occur in individuals with homozygous FH.
• Corneal arcus (white, gray, or blue opaque ring in the corneal margin). Because this becomes increasingly common in the general population with age, it is only diagnostic in younger individuals, particularly before age 45 years.

Note: As statin treatment has become more common, it is possible that individuals have fewer visible signs of FH, complicating the application of the diagnostic criteria.

Family history of any of the following

• Familial hypercholesterolemia
• High levels of LDL-C
• Early-onset (i.e., age <50 years) CAD (especially myocardial infarction)
• Xanthomas

Identification of a pathogenic variant in a gene known to be associated with FH (see Table 1) is the gold standard for diagnosis accepted in many countries [Nordestgaard et al 2013].

• The likelihood of identifying a pathogenic variant by molecular testing increases with higher LDL-C levels.
• In the United States, genetic testing is recommended when other laboratory tests have not definitively established the diagnosis of FH.

Molecular genetic testing approaches can include serial single-gene testing and use of a multigene panel:

• Serial single-gene testing can be considered. Sequence analysis of LDLR is performed first and followed by LDLR deletion/duplication analysis if no pathogenic variant is found. Sequence analysis of APOB and PCSK9 can be performed next if no pathogenic variant is found.
• A multigene panel that includes APOB, LDLR, PCSK9 and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included and the sensitivity of multigene panels vary by laboratory and over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Clinical Description

Familial Hypercholesterolemia (FH)

Coronary artery disease (CAD) and cardiovascular disease (CVD). Elevated LDL cholesterol (LDL-C) leads to atherosclerotic plaque deposition in the coronary arteries and proximal aorta at an early age, leading over time to an increased risk for cardiovascular disease (CVD), which by definition includes coronary artery disease (CAD) (manifest as angina and myocardial infarction) and stroke [Scientific Steering Committee 1991, Versmissen et al 2008, Elis et al 2011, Raal & Santos 2012]. In FH, CAD is the more common cardiovascular disease; stroke occurs more rarely and some evidence suggests that the risk for stroke may not be greater than in the general population [Huxley et al 2003].

All individuals with FH should be considered “high risk” (i.e., increased ~20-fold) for CAD. Recent data suggest that individuals with an LDL-C >190 mg/dL (>4.9 mmol/L) and a pathogenic variant in one of the genes listed in Table 1 have a 22-fold increased risk for CAD while those without a pathogenic variant have a sixfold increased risk for CAD over the general population [Khera et al 2016].

Natural history studies from the pre-statin era suggest that untreated men are at 50% risk for a fatal or non-fatal coronary event by age 50 years; untreated women are at 30% risk by age 60 years [Slack 1969, Stone et al 1974, Civeira 2004, Goldberg et al 2011, Reiner et al 2011]. See Figure 1. Of note, standard Framingham or other risk classification schemes are not applicable to persons with FH [Goldberg et al 2011, Reiner et al 2011, Nordestgaard et al 2013].

Figure 1.

LDL cholesterol burden in individuals with or without familial hypercholesterolemia as a function of the age of initiation of statin therapy Data derived from Starr et al [2008] and Huijgen et al [2012]. Figure from Nordestgaard et al [2013]; used by (more...)

Lipid-lowering therapy with statin-based regimens (see Management, Treatment of Manifestations) significantly increases survival [Nordestgaard et al 2013, Vuorio et al 2013] and reduces morbidity [Versmissen et al 2008, Elis et al 2011]. Additional medications such as ezetimibe, bile acid binding resins, or PCSK9 inhibiters are often necessary to achieve optimal LDL-C reduction [Gidding et al 2015].

Data from the CASCADE-FH registry reveals that upwards of 61% of adults with FH have at least one modifiable cardiovascular risk factor. Coronary heart disease was reported in 47% of men with FH, with a median age of onset of 47 years. Coronary heart disease was reported in 29% of women with FH, with a median age of onset of 55 years. A high-dose statin was being taken by 42% of individuals with FH, 33% of individuals were on a low-dose statin, and 25% of individuals were not taking a statin. The most common reasons for lack of statin use included intolerance or allergy (60%), patient preference (11%), physician preference (11%), pregnancy (3%), cost (1%), and clinical trial participation (1%). Twenty-five percent of treated individuals had an LDL-C below 100 mg/dL and 41% of individuals achieved a 50% or greater reduction in LDL-C from untreated values [deGoma et al 2016].

Xanthomas are patches of yellowish cholesterol buildup in particular areas of the body as a result of extremely high levels of LDL-C. Xanthomas may worsen with age in persons who are not treated. In persons treated with LDL-C-lowering therapy, the xanthomas can become smaller. Common locations:

• Xanthomas often occur around the eyelids (xanthelasma palpebrarum or more commonly just xanthelasma) [Dey et al 2013].
• Tendonous xanthomas can occur in the elbows, hands, knees, and feet, particularly the Achilles tendon [Tsouli et al 2005, Elis et al 2011]. These are historically described in 30%-50% of persons with FH, although more recent studies show a lower prevalence likely due to widespread statin use [Perez de Isla et al 2016].
• Interdigital xanthomas (between the fingers) occur in individuals with homozygous FH.

Corneal arcus (white, gray, or blue opaque ring in the corneal margin). Because corneal arcus becomes increasingly common in the general population with age, it is only diagnostic in younger individuals, particularly before age 45 years.

Phenotype Correlations by Gene

APOB. FH caused by a heterozygous APOB pathogenic variant is reported to be less severe than FH caused by a heterozygous pathogenic variant in LDLR or PCSK9 [Hopkins et al 2011].

Genotype-Phenotype Correlations

LDLR. Complete loss-of-function variants in LDLR generally lead to more severe disease due to higher LDL-C levels [Khera et al 2016]. Partial loss-of-function variants in LDLR result in less severe disease due to lower LDL-C levels.

Penetrance

APOB. Penetrance for FH can be incomplete in persons with a heterozygous APOB pathogenic variant [Fahed & Nemer 2011].

LDLR. Recent findings suggest that only 73% of individuals with a heterozygous LDLR pathogenic variant have an LDL level >130 mg/dL, suggesting lower penetrance than previously proposed [Khera et al 2016].

PCSK9

• Penetrance is approximately 90% in persons heterozygous for the c.381T>A (p.Ser127Arg) pathogenic variant.
• Penetrance in persons heterozygous for the p.Asp374Tyr pathogenic variant is high, with FH manifesting at a young age [Naoumova et al 2005].
• Penetrance for other heterozygous PCSK9 pathogenic variants remains largely unknown [Cariou et al 2011].

Prevalence

The prevalence of FH in the general population has traditionally been cited as 1:500. However, emerging data suggest that the prevalence of FH is higher in white/European populations, perhaps as common as 1:200 [Benn et al 2012, Nordestgaard et al 2013].

FH is more common (due to founder effects) in several populations (Table 2). Of note, data are limited on prevalence of FH in most African and South Asian/Indian populations.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with familial hypercholesterolemia (FH) the following evaluations are recommended in adults and children:

• Measurement of pre-treatment lipid values and lipoprotein(a) levels when possible
• Exclusion of concurrent illnesses (kidney disease, acute myocardial infarction, infection) that can affect lipid values
• Lipid panel including total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides
• Consultation with a lipid specialist or clinician with expertise in FH
• Recommended in some guidelines: noninvasive imaging modalities in children (e.g., measurement of carotid intima-media thickness) to help inform treatment decisions [Martin et al 2013]
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Prevention of Primary Manifestations

Preventive measures include the following:

• Statin-based therapy with addition of other medications as needed
• Reduced intake of saturated fat
• Increased intake of soluble fiber to 10-20 g/day
• Increased physical activity
• Not smoking

Surveillance

Children. Guidelines for the management of children have been published by multiple national and international organizations [Daniels et al 2008, DeMott et al 2008, Descamps et al 2011, Martin et al 2013] (see Published Guidelines / Consensus Statements).

A child who has a family history of FH or of premature CAD, who is heterozygous for the FH pathogenic variant in his or her family, or who has an elevated serum cholesterol concentration should have lipid levels checked starting as early as age two years [Goldberg et al 2011]. It is reasonable to check a non-fasting lipid level first and, if borderline, to follow with measurement of LDL-C. Some guidelines state that elevation of two consecutive measures of LDL-C are needed to confirm a diagnosis of FH [Martin et al 2013].

An LDL-C level of >130 mg/dL (>3.4 mmol/L) in a child is suspicious for FH and an LDL of >160 mg/dL (>4.1 mmol/L) is relatively specific for FH.

During treatment, individuals of any age with:

• FH should have lipid levels monitored as recommended;
• HoFH should be monitored with various imaging modalities (including echocardiogram, CT angiogram, and cardiac catheterization) as recommended [Raal & Santos 2012].

Agents/Circumstances to Avoid

The following should be avoided:

• Smoking
• High intake of saturated and trans unsaturated fat
• Excessive intake of cholesterol
• Sedentary lifestyle
• Obesity
• Hypertension
• Diabetes mellitus

Evaluation of Relatives at Risk

The CDC has classified FH as a Tier 1 condition indicating a significant benefit from performing family-based cascade screening using cholesterol testing with or without DNA analysis on relatives of affected persons with FH in order to identify previously unknown cases of FH and provide those people with life-saving treatment. Early diagnosis and treatment of relatives at risk for FH can reduce morbidity and mortality [Goldberg et al 2011, Ned & Sijbrands 2011, Reiner et al 2011].

The genetic status of at-risk family members can be clarified by EITHER of the following:

• Molecular genetic testing if the pathogenic variant has been identified in an affected family member
• Measurement of LDL-C level. Table 4 provides age-specific total cholesterol and LDL-C levels [Williams et al 1993]. Note: Age-specific LDL cut-offs are also available based on more contemporary data from the United Kingdom [Starr et al 2008].

Of note, all national and international guidelines for FH call for “cascade testing” of relatives at risk (i.e., systematic testing of first- and second-degree relatives of the index case [proband]). Evidence supports the use of genetic testing in cascade testing algorithms to improve the detection of FH [DeMott et al 2008, Wierzbicki et al 2008, Wald et al 2016].

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Statins are contraindicated during pregnancy; women with FH who are considering a pregnancy should be counseled of this risk and statins should be discontinued prior to conception.

Pregnant women should incorporate all the other recommended lifestyle changes including low saturated and trans unsaturated fat intake, no smoking, and high dietary soluble fiber intake (see Agents/Circumstances to Avoid).

Pharmacologic treatment during pregnancy

• Statins are contraindicated in pregnancy due to concerns for teratogenicity. The use of statins during human pregnancy has not definitively been associated with adverse fetal outcome; however, the role of cholesterol in embryologic development has led to theoretic concerns about the effect of these medications on a developing fetus and a recommendation that alternative medications be considered during pregnancy and lactation. Nursing mothers should not take statins.
• Bile acid binding resins (colesevelam, cholestyramine) are generally considered safe (Class B for pregnancy). Based primarily on animal studies, cholestyramine use during pregnancy has not been associated with an increased risk of fetal anomalies. However, use of cholestyramine could theoretically cause depletion of maternal fat-soluble vitamins, including vitamin K.
• LDL apheresis is also occasionally used.
• Regarding other agents:
  • PCSK9 inhibitors. Use during pregnancy has not been well studied.
  • Ezetimibe. Use during human pregnancy has not been well studied.
  • Niacin. The use of pharmacologic doses of niacin, an essential vitamin, has not been studied in human pregnancy. The recommended upper limit of niacin intake during pregnancy is 30-35 mgs/day; higher doses have been associated with toxicity.

Therapies Under Investigation

CAD outcome trials of PCSK9 inhibitors are currently underway.

Search ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

Heterozygous familial hypercholesterolemia (FH, HeFH) and homozygous familial hypercholesterolemia (HoFH) are inherited in an autosomal dominant manner.

Risk to Family Members – Heterozygous Familial Hypercholesterolemia (FH)

Parents of a proband

• Almost all individuals diagnosed with FH have an affected parent.
• A proband with FH may have the disorder as the result of a de novo pathogenic variant. Because simplex cases (i.e., a single occurrence in a family) have not yet been evaluated sufficiently to determine if the pathogenic variant occurred de novo, the proportion of FH caused by de novo pathogenic variants is unknown but appears to be very low.
• If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, two possible explanations are germline mosaicism in a parent or a de novo pathogenic variant in the proband. Although no instances of germline mosaicism have been reported, it remains a possibility.
• Recommendations for the evaluation of parents of a proband with an apparent de novo pathogenic variant include molecular genetic testing if the pathogenic variant has been identified in the proband, or cholesterol testing if the pathogenic variant has not been identified in the proband. Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed.
• Note: Although most individuals diagnosed with FH have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent.

Sibs of a proband

• The risk to the sibs of the proband depends on the genetic status of the proband’s parents.
• If a parent of the proband is affected or has a pathogenic variant, the risk to the sibs is 50%.
• If both parents of the proband are affected with FH or have a pathogenic variant, the risk to sibs of having FH is 50%, the risk to sibs having HoFH is 25%.
• When the parents are clinically unaffected, the risk to the sibs of a proband appears to be very low.
• The sibs of a proband with clinically unaffected parents are still at increased risk for familial hypercholesterolemia because of the possibility of reduced penetrance in a parent. However, this is a very unlikely scenario.
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is low but greater than that of the general population because of the theoretic possibility of parental germline mosaicism.

Offspring of a proband

• Each child of an individual with FH has a 50% chance of inheriting the pathogenic variant.
• If both parents of a child are affected with FH, the child has a 50% chance of having FH and a 25% chance of having HoFH.

Other family members. The risk to other family members depends on the status of the proband's parents. If a parent is affected or has a pathogenic variant, his or her family members may be at risk.

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant identified in the proband, the pathogenic variant is likely de novo. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Risk to Family Members – Homozygous Familial Hypercholesterolemia (HoFH)

Parents of a proband

• The parents of an affected individual are obligate heterozygotes and thus have one familial hypercholesterolemia-related pathogenic variant.
• Individuals with one pathogenic variant have FH.

Sibs of a proband. The risk to sibs of having FH is 50%; the risk to sibs of having HoFH is 25%.

Offspring of a proband. The offspring of an individual with HoFH are obligate heterozygotes for a pathogenic variant; thus, all will have FH.

Other family members. Sibs of the proband's parents are at 50% risk of having a pathogenic variant and, thus, FH.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Specific risk issues. Individuals inheriting pathogenic variants from both parents will develop a severe form of familial hypercholesterolemia (HoFH).

Predictive genetic testing for asymptomatic adult family members at risk for FH requires prior identification of the pathogenic variant in the family.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the pathogenic variant has been identified in a family member with FH (or both pathogenic variants have been identified in a family member with HoFH), prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Published Guidelines / Consensus Statements

• American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines; American Association for Thoracic Surgery; American Society of Echocardiography; American Society of Nuclear Cardiology; Heart Failure Society of America; Heart Rhythm Society; Society for Cardiovascular Angiography and Interventions; Society of Thoracic Surgeons, Gersh BJ, Maron BJ, Bonow RO, Dearani JA, Fifer MA, Link MS, Naidu SS, Nishimura RA, Ommen SR, Rakowski H, Seidman CE, Towbin JA, Udelson JE, Yancy CW. 2011 ACCF/AHA guideline for the diagnosis and treatment of hypertrophic cardiomyopathy: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Available online. 2011. Accessed 4-17-18. [PubMed: 22068435]
• Daniels SR, Greer FR; Committee on Nutrition. 2008. Lipid screening and cardiovascular health in childhood. Available online. 2008. Accessed 4-17-18. [PubMed: 18596007]
• DeMott K, Nherera L, Shaw EJ, Minhas R, Humphries SE, Kathoria M, Ritchie G, Nunes V, Davies D, Lee P, McDowell I, Neil A, Qureshi N, Rowlands P, Seed M, Stracey H, Thorogood M, Watson M. Clinical guidelines and evidence review for familial hypercholesterolæmia: the identification and management of adults and children with familial hypercholesterolæmia. London: National Collaborating Centre for Primary Care and Royal College of General Practitioners. Available online. 2008. Accessed 4-17-18.
• 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, pædiatricians, nutritionists, gastroenterologists, general practitioners and a patient organization. 2011. [PubMed: 21762914]
• 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; National Lipid Association Expert Panel on Familial Hypercholesterolemia. Familial hypercholesterolemia: screening, diagnosis and management of pediatric and adult patients: clinical guidance from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. 2011. [PubMed: 21600525]
• Hopkins PN, Toth PP, Ballantyne CM, Rader DJ; National Lipid Association Expert Panel on Familial Hypercholesterolemia. Familial hypercholesterolemias: prevalence, genetics, diagnosis and screening recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. 2011. [PubMed: 21600530]
• Ito MK, McGowan MP, Moriarty PM; National Lipid Association Expert Panel on Familial Hypercholesterolemia. 2011. Management of familial hypercholesterolemias in adult patients: recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. 2011. [PubMed: 21600528]
• Martin AC, Coakley J, Forbes DA, Sullivan DR, Watts GF. Familial hypercholesterolæmia in children and adolescents: a new pædiatric model of care. 2013. [PubMed: 23252991]

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Revision History

• 8 December 2016 (sw) Comprehensive update posted live
• 2 January 2014 (me) Review posted live
• 5 August 2013 (jl) Original submission