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Homozygous Familial Hypercholesterolemia


Homozygous familial hypercholesterolemia (HoFH) is an inherited condition which leads to extremely elevated levels of low-density lipoprotein (LDL) cholesterol.

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HoFH is a genetic condition with varying clinical presentation; the type of mutation that the patient is affected by determines the severity of the manifestations. Patients who are affected by the disease have LDL cholesterol levels that amount to over 500 mg/dL, irrespective of their age.

One of the most typical manifestations of HoFH that can be macroscopically observed is xanthomata. They usually develop before the age of ten years old and are located in the ankles, wrists, natal cleft and other regions. Planar xanthomata of the space in-between the digits are the single pathognomonic sign of HoFH, but they may also be found in locations where the skin is subjected to increased levels of friction. Tendinous xanthomata are also observed, mostly in the Achilles and extensor tendons of the hand, but do not appear during the first years of an individual's life. Other signs that may accompany xanthomata but are not indicative of HoFH are xanthelasma and arcus cornealis.

In the case that the diagnosis of HoFH is not established during infancy or childhood due to the absence of xanthomata, it is usually diagnosed after the cardiovascular atheromatic disease has developed in young adults or even adolescents. The key features of manifestations of cardiovascular disease may include the following:

  • Ischemic phenomena
  • Supravalvular aortic stenosis
  • Coronary ostial stenosis
  • Vascular bruits
Chest Discomfort
  • A 72-year-old woman who had been diagnosed as homozygous familial hypercholesterolemia was admitted for chest discomfort.[ncbi.nlm.nih.gov]
  • Skin examination showed: intertriginous xanthomas of feet and hands, tuberous xanthomas in knees and elbows, tendinous xanthomas in Achilles tendon and xanthomas in the gluteal region, associated with corneal arc bilaterally.[ncbi.nlm.nih.gov]
  • Physical examination revealed tuberous xanthomas on the processus olecrani, as well as smaller tendinous and tuberous xanthomas on the hands. Both tendinous and tuberous xanthomas may occur in patients with HFH.[ncbi.nlm.nih.gov]
  • Xanthomas The high cholesterol level may result in the build-up of cholesterol deposits in the skin and tendons as well – xanthomas. Skin xanthomas (cutaneous xanthomas): particularly on eyelids and between the fingers.[aoporphan.com]
  • The index cases were 24-year-old identical twin sisters with long-standing tendon xanthomas and high low-density lipoprotein cholesterol (LDL-C 10 mmol/L) but no coronary heart disease.[ncbi.nlm.nih.gov]
  • In addition, the younger sister had yellowish streaks of plane xanthoma on the side and back of the neck [Figure 2] a], periumbilical xanthoma [Figure 2] b] and two subcutaneous soft swellings below the knees [Figure 2] c].[e-ijd.org]
Skin Lesion
  • We report the case of a 12-year-old male who developed corneal arcus and multiple skin lesions with a 10-year history of xanthomas. The lesions appeared over his fingers, hands, elbows, knees, buttocks and feet.[ncbi.nlm.nih.gov]
  • Case Report A 12-year-old male, whose father was a LDL receptor (LDL-R) mutation carrier, developed corneal arcus and multiple skin lesions with a 10-year history of xanthomas.[ijo.in]
  • Physical examination may find xanthomas and xanthelasmas (skin lesions caused by cholesterol rich lipoprotein deposits), and cholesterol deposits in the eye called corneal arcus.[genome.gov]
  • lesions, such as cutaneous xanthomas at birth or by early childhood (eg, planar xanthomas, tuberous xanthomas; later, tendon xanthomas) Corneal arcus may be present and is sometimes circumferential Murmur of aortic stenosis may be present Most patients[emedicine.medscape.com]
Arcus Senilis
  • Yellow deposits of cholesterol-rich fat may be seen in various places on the body such as around the eyelids (known as xanthelasma palpebrarum ), the outer margin of the iris (known as arcus senilis corneae ), and in the tendons of the hands, elbows,[en.wikipedia.org]
Corneal Deposit
  • deposits are associated with normal aging, but should raise suspicion of FH in patients from childhood to early middle age ( Treating FH Nearly 100 percent of FH patients require statins.[ohsu.edu]
  • Flu-like symptoms, defined as any one of the following: influenza-like illness, pyrexia, chills, myalgia, arthralgia, malaise or fatigue and occurring within 2 days of injection, have been reported more frequently in patients receiving KYNAMRO (30%) versus[news.genzyme.com]
  • ., pyrexia, chills, myalgia, arthralgia, malaise, fatigue) compared with 16% of those receiving placebo [ 29 ]. Laboratory abnormalities in the phase III HoFH trial were primarily characterized by elevated liver transaminases.[intechopen.com]
  • […] symptoms Homozygous FH Signs and symptoms of homozygous FH in children include the following: Symptoms consistent with ischemic heart disease, peripheral vascular disease, cerebrovascular disease, or aortic stenosis Articular symptoms such as tendonitis or arthralgias[emedicine.medscape.com]
  • Regeneron commercializes medicines for eye diseases, high LDL-cholesterol, atopic dermatitis and a rare inflammatory condition and has product candidates in development in other areas of high unmet medical need, including rheumatoid arthritis, asthma,[prnewswire.com]
  • Therefore, arthritis and tendinitis may attract attention to the diagnosis of patients with FH. [3] Xanthomas develop because of lipid leakage from the vasculature into the surrounding tissues, where macrophages subsequently phagocytose these lipids.[e-ijd.org]
  • Until June, 2017, she was admitted to our center due to edema, oliguria, and dyspnea during exertion, which was attributed to a recent respiratory infection. Homozygous FH (HoFH), CHD, and IHF.[ncbi.nlm.nih.gov]


Patients affected by homozygous familial hypercholesterolemia, typically exhibit abnormally high LDL cholesterol blood levels, from a very young age. Levels vary but untreated HoFH generally manifests with LDL levels that exceed 500 mg/dL; other studies indicated that even when treated, LDL levels vary between 200 mg/dL and 700 mg/dL [13] [14] [15]. the condition is most often diagnosed when a dermatologist suspects it due to the presence of xanthomatous lesions on the skin or when there is a family history of inherited hypercholesterolemia since children do not usually undergo blood testing for cholesterol [16]. A genetic test may also help to reveal LDLR mutations or mutations affecting genes that partake in the metabolism of LDL; they contribute little, however, to the actual diagnosis, since up to 40% of HoFH patients have mutations that cannot be traced [17].

Coronary Angiogram Abnormal
  • Markers of atherosclerosis correlated significantly with age at which lipid-lowering treatment was initiated (abnormal coronary angiogram, abnormal aortic valve using echocardiography, and high calcium score using electron beam computed tomography; all[ncbi.nlm.nih.gov]


The guidelines that are followed in cases of HoFH treatment as established by the EAS include four specific recommendations:

  • Statins, lipoprotein apheresis, and lifestyle adaptations should be applied as soon as the diagnosis is established

The adaptation of a healthier lifestyle does not affect cholesterol levels in true HoFH homozygotes; it does, however, reduce the severity of cardiovascular disease and modifications are mandatory [18] [19]. Statins are a powerful tool that can considerably reduce LDL cholesterol levels and include ezetimibe, ezetimibe, and atorvastatin (Liptruzet), alongside niacin, bile acid sequestrants and HMG-CoA reductase inhibitors [20]. LDL apheresis is performed when the LDL receptors are absent or completely dysfunctional and involves the removal of certain LDL molecules that carry specific characteristics. Apheresis contributes to the amelioration of the triglyceride, VLDL, and lipoprotein a profile, without lowering HDL concentrations. This therapeutic option is usually not applied due to its high cost [21] [22].

  • Lipoprotein apheresis needs to be initiated between the ages of 5 and 8 years old
  • LDL cholesterol levels should amount to <100 mg/dL (adults), <70 mg/dL (adults with cardiovascular disease) and <135 (children)
  • Newer drugs such as mipomersen, evolocumab and lomitapide can be considered as possible options if the aforementioned therapies fail to control LDL concentration in high-risk patients [23] [24] [25] [26] [27].

Other than pharmaceutical conservative treatment, surgical therapy can also prove beneficial to patients with HoFH. Portacaval anastomosis can significantly reduce LDL cholesterol levels and target xanthomata, aortic and coronary lesions.


Homozygous familial hypercholesterolemia is accompanied by a poor prognosis, with the patients surviving averagely until the age of 33 years [11]. A negative prognostic factor that induces the earlier development of atheromatic plaques is the duration of the period that the patient was subjected to high LDL cholesterol levels without proper treatment. HoFH causes supravalvular aortic stenosis, which greatly increases the risk of a myocardial infarction [12].


The clearance of LDL cholesterol from the circulation is performed via the low-density lipoprotein receptor (LDLR) which is responsible for the transportation of the molecule into the cell, so as to enable its catabolism. HoFH is caused by a genetic mutation that affects either the gene that encodes for LDLR or various genes that partake in the metabolism of LDL. The condition is passed down from parents to offspring via the autosomal co-dominant or recessive pattern, with the former being the most common pattern of inheritance.

Up to this day, four distinct mutations have been identified with regard to the inheritance of HoFH; all affect the LDLR gene. More specifically, the majority of the patients affected by HoFH exhibit defects in both LDLR alleles. The defects may be identical (true homozygote patients) or different (compound homozygotes), with the specific pattern of inheritance being autosomal co-dominant. Should only one LDLR allele be defective, the condition that arises is called heterozygous familial hypercholesterolemia and presents less severely than HoFH. A second gene that has been linked to HoFH is the autosomal recessive hypercholesterolaemia (ARH) adaptor protein 1 gene: both alleles are required to be defective in order for HoFH to occur since the pattern of inheritance is autosomal recessive in this case.

ApoB100 is a third gene that is associated with the condition and the protein it encodes for acts as a ligand for LDLR. Defects in both alleles do induce HoFH, albeit its manifestations are considerably milder [3] [4]. Lastly, proprotein convertase subtilisin/Kexin type 9 (PCSK9) is a protease that is produced by hepatocytes and inhibits the re-circulation of LDLR. Mutations that affect both PCSK9 alleles lead to homozygous familial hypercholesterolemia, also with a mild phenotype [4].

It is also possible for a patient to exhibit mutations in a combination of genes associated with the LDL cholesterol metabolic pathway.


During the previous years, HoFH was considered a very rare genetic disorder, whose frequency was believed to amount to 1 in 1,000,000 [1]. Regionally higher frequencies, such as those of the French Canadians or the Christian Lebanese has been a fact; they have historically been attributed to the loss of genetic diversity when a separate community if established by a small group of people, also known as the founder effect [5]. According to more recent studies, the actual frequency of HoFH has risen to 1 in 160,000 to 1 in 300,000 individuals [6].

Sex distribution
Age distribution


Homozygous familial hypercholesterolemia is an inherited disorder that leads to abnormally high LDL cholesterol levels and may lead to devastating complications and death, if not appropriately treated. The most common mutations affect the LDLR gene and cause a severe phenotype; other mutations affect genes that influence the functionality of LDLR in an indirect or direct way, such as ApoB100, PCSK9, and ARH [7]. In the case when both LDLR alleles evince the exact same genetic defect, a patient is considered a true homozygote, whereas a patient who carries two distinct mutations in the LDLR alleles is a compound homozygote [8]. In some cases, two different genes are genetically impaired [9], something which results in HoFH with a milder phenotype. HoFH is a condition that needs a prompt and accurate diagnosis and treatment, as the lack thereof may lead to death due to cardiovascular causes even as early as in childhood [10]. Even with proper treatment, the majority of the patients are diagnosed with HoFH-induced cardiovascular disease early during adulthood.


HoFH is an inherited disorder and can therefore not be prevented. However, the risk of cardiovascular disease can be reduced by careful monitoring, medications that reduce LDL cholesterol levels, aerobic exercise and weight loss.


Homozygous familial hypercholesterolaemia (HoFH) is a rare genetic disorder which leads to extremely augmented levels of blood cholesterol that exceed the value of 500 mg/dL. The clinical picture is completed by the presence of xanthomata in various regions of the body, as well as premature atherosclerotic cardiovascular disease (AVCD).

The majority of the HoFH occurrences are induced by defects in the LDLR gene, which encodes for the LDLR protein; the latter is responsible for the endocytosis of LDL cholesterol so that it can be metabolised and excreted [1]. Other mutations that affect genes that regulate a procedure involved in the metabolism of cholesterol also lead to HoFH, such as mutation to the PCSK9, APOB, and LDLRAP1 genes. HoFH is accompanied by a poor prognosis even when treatment is administered and the average age of survival does not exceed 30 years. This is attributed to the fact that the condition is usually diagnosed when extensive cardiovascular atherosclerotic lesions have developed. Thus, it is imperative for the disease to be diagnosed as early as possible; a potential aortic stenosis and ostial occlusion need to be evaluated thoroughly [2].

Treatment is largely conservative and consists of statin therapy, apheresis and lifestyle modifications. Newer drugs such as mipomersen and evolocumab have been recently added to the therapeutic regime. Surgical therapy is another option, as portacaval anastomosis seems to reduce the level of LDL cholesterol through an unknown mechanism.

Patient Information

Cholesterol is a lipid molecule that takes part in multiple vital functions directly related to survival. The molecule is necessary for the cells so that they can acquire their outer cellular membrane and participates in the production of bile acids and hormones. The two types of cholesterol that have a great significance to every individual are high-density lipoprotein cholesterol (HDL) and low-density lipoprotein cholesterol (LDL). The latter, LDL cholesterol is viewed as the negative type of cholesterol, as it contributes to the buildup of fatty plaques within the arterial vessel walls and causes heart disease. On the other hand, HDL cholesterol is the beneficial cholesterol type, which participates in vital functions and also helps to remove a part of LDL cholesterol from the bloodstream.

LDL cholesterol is broken down and excreted from the liver: the LDLR protein is a molecule that recognises LDL molecules and helps them to enter the cells so that they can be metabolised. In this way, LDLR is required, so that a considerable amount of unhealthy cholesterol can be removed from the blood. The protein is encoded for by the LDLR gene.

Homozygotic familial hypercholesterolemia (HoFH) is a genetic disorder that can be passed down from parents to offspring via a couple of different inheritance pathways. Hypercholesterolemia means that the affected individual will have extremely high levels of LDL cholesterol and total cholesterol (HDL+LDL) in their blood, familial means that the condition is inherited and homozygotic refers to the genetic pattern of the disease: the person suffering from HoFH has two genes, one from each parent, which display the same mutation. The genetic mutations that cause HoFH are usually found in the LDLR gene; thus, the LDLR protein that is produced is dysfunctional, fails to transport LDL cholesterol into the cells and its excretion from the organism cannot be completed. As a result, high levels of LDL cholesterol are found in the blood with devastating effects for the individual, as atherosclerosis, heart disease and related conditions arise. Other genes that participate in the metabolism of cholesterol may also be affected and lead to HoFH.

Homozygotic familial hypercholesterolemia is usually diagnosed within the first years of a person's life, as it leads to the development of xanthomata, namely yellow patches, on various locations of the skin. A dermatologist is a doctor that will most likely observe such a sign and recommend a blood cholesterol test. If it is not diagnosed early, HoFH may lead to heart disease due to atherosclerosis. The onset of heart disease may be delayed in patients who are diagnosed and treated early. Typical signs that cardiac disease presents include shortness of breath, chest pain or a rapid heartbeat.

HoFH is diagnosed by a blood cholesterol examination that is expected to show total cholesterol levels > 300 mg/dL in adults and >250 mg/dL in children. LDL cholesterol levels are usually >200 mg/dL in children and >220 mg/dL in adults; under some circumstances they may even reach values exceeding 500 mg/dL. Xanthomata at a young age are highly suggestive of HoFH and the premature onset of the cardiac disease is also a very frequently observed comorbidity. Treatment consists of lifestyle adaptations so that the patient's lifestyle can be healthier, statin therapy which lowers cholesterol levels, apheresis which is a procedure employed in order to remove a part of LDL cholesterol with, particularly dangerous characteristics. Newer drugs have exhibited a possible success in the treatment of cholesterol and are being used in combination with the older ones, in order to achieve a better therapeutic result.



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Last updated: 2018-06-21 17:09