While those suffering from homozygous FCH generally present in childhood or adolescence, heterozygotes don't usually experience any symptoms until early adulthood [1]. Hypercholesterolemia is the hallmark of both variants and is associated with the deposition of cholesterol-rich material in distinct tissues:

• In the cornea, it leads to the formation of an arcus senilis, a light gray or yellowish ring around the rim of the iris.
• Excess lipids may also be deposited underneath the skin, giving rise to the formation of xanthelasmas. They are yellowish-orange papules or plaques that preferentially develop on the eyelids or elsewhere in the face.
• Tuberous xanthomas are nodular cutaneous xanthomas that develop on the extensor surfaces of joints and pressure areas, such as the elbows, knees, and heels.
• Firm subcutaneous nodules under unaltered skin may correspond to tendon xanthomas. Predilection sites are the extensor tendons of the hand and the Achilles tendon [2].

Furthermore, cholesterol-rich lipids are deposited in the arteries. While this is not readily visible, it may induce life-threatening cardiovascular disease. Atherosclerosis and coronary heart disease are frequent findings in FCH patients, and they may be diagnosed at the age of just 3 years [3]. Furthermore, thickening of the aortic valve and aortic root may lead to aortic regurgitation or stenosis [1]. The descending aorta, carotid, renal, and ileo-femoral arteries may also be affected [4].

• Coronary Atherosclerosis

  Pediatric patients with familial hypercholesterolemia may present with premature coronary atherosclerosis requiring coronary artery bypass grafting. In situ internal mammary artery grafts should be the graft of choice. [ncbi.nlm.nih.gov]

• Pallor

  Less common clinical features include intestinal bleeding, pallor, anemia, irritability, diarrhea, seizures and encephalopathy [ 10, 11 ]. [mdpi.com]

• Hypertension

  Physical examination revealed hypertension, subfebrile temperature, and costovertebral angle tenderness. [ncbi.nlm.nih.gov]

  Evidence from 58 Utah families for a syndrome present in approximately 12% of patients with essential hypertension, JAMA, 1988, vol. 259 (pg. 3579 - 3586 ) 14 Apolipoprotein, low density lipoprotein subfraction, and insulin associations with familial [dx.doi.org]

• Family History of Heart Disease

  Other signs and symptoms of hyperlipoproteinemia include: pancreatitis (type 1) abdominal pain (types 1 and 5) enlarged liver or spleen (type 1) lipid deposits or xanthomas (type 1) family history of heart disease (types 2 and 4) family history of diabetes [healthline.com]

  Being aware of the key features of FH, including a family history of heart disease before the age of 60 and/or a very high level of cholesterol in the blood, is crucial for people to be able to recognise their own risk and seek advice if necessary. [publichealthmatters.blog.gov.uk]

  Patients with an extensive family history of heart disease should also be screened by measuring Lp(a) levels. [merckmanuals.com]

• Arthralgia

  Arcus senilis: A white-colored ring around the cornea Arthralgia (joint pain) Tendonitis (inflamed tendons) History of unusual skin lesions At least one parent with severe hypercholesterolemia The most significant consequence of familial hypercholesterolemia [ada.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.com]

  In pooled phase III trials that included all patients with hypercholesterolemia, 30% of patients experienced flu‐like symptoms (e.g., pyrexia, chills, myalgia, arthralgia, malaise, fatigue) compared with 16% of those receiving placebo [29]. [intechopen.com]

• Arcus Senilis

  senilis (gray or white discoloring of the eye’s cornea. [availclinical.com]

  Hypercholesterolemia is the hallmark of both variants and is associated with the deposition of cholesterol-rich material in distinct tissues: In the cornea, it leads to the formation of an arcus senilis, a light gray or yellowish ring around the rim of [symptoma.com]

  Arcus senilis: A white-colored ring around the cornea Arthralgia (joint pain) Tendonitis (inflamed tendons) History of unusual skin lesions At least one parent with severe hypercholesterolemia The most significant consequence of familial hypercholesterolemia [ada.com]

• Xanthoma

  Tuberous xanthomas are nodular cutaneous xanthomas that develop on the extensor surfaces of joints and pressure areas, such as the elbows, knees, and heels. Firm subcutaneous nodules under unaltered skin may correspond to tendon xanthomas. [symptoma.com]

  Xanthoma should be considered in cases with swellings in the Achilles tendon. Total resection is necessary to avoid recurrence of the xanthomas. [ncbi.nlm.nih.gov]

  Image of tendon xanthoma, a pathognomonic physical examination finding in patients with familial hypercholesterolemia. Figure. Image of tendon xanthoma, a pathognomonic physical examination finding in patients with familial hypercholesterolemia. [doi.org]

  Diffuse plane xanthomas Xanthoma disseminatum Xanthoma-like lesions due to a rare form of histiocytosis. Lipid metabolism is normal. [dermnetnz.org]

• Xanthelasma

  Her mother and maternal grandmother both had a history of hypercholesterolemia and had developed extensive xanthelasma palpebrarum from early adult life. [ncbi.nlm.nih.gov]

  […] not be associated with hyperlipidaemia See more images of xanthelasma ... [dermnetnz.org]

• Skin Lesion

  After two yr, liver transplantation normalized LDL-cholesterol levels and completely resolved the skin lesions. [ncbi.nlm.nih.gov]

  Definition of familial hypercholesterolemia : an inherited metabolic disorder marked by excess accumulation of LDL cholesterol in the blood resulting especially in atherosclerosis and irregular yellow skin lesions Examples of familial hypercholesterolemia [merriam-webster.com]

  A xanthoma is a skin lesion caused by the accumulation of fat in macrophage immune cells in the skin and more rarely in the layer of fat under the skin. [dermnetnz.org]

  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]

  Arcus senilis: A white-colored ring around the cornea Arthralgia (joint pain) Tendonitis (inflamed tendons) History of unusual skin lesions At least one parent with severe hypercholesterolemia The most significant consequence of familial hypercholesterolemia [ada.com]

• Stroke

  These drugs help lower your risk of heart attack and stroke. [nlm.nih.gov]

  For example, according to the CDC Division of Heart Disease and Stroke Prevention (DHDSP) public health departments can work to prevent and control high blood cholesterol and reduce the burden of heart disease and stroke by promoting activities that can [cdc.gov]

  Your doctor may suspect FH if: a routine blood test shows you have high levels of cholesterol you have a heart attack or stroke, especially if you are under 50 when it happens other members of your family have a history of premature heart disease or stroke [croi.ie]

  People with FH are unable to process the body’s natural supply of cholesterol, leading to very high levels of “bad” cholesterol that can block arteries and lead to a heart attack or stroke. [euractiv.com]

  This includes problems like heart attacks, strokes, and even narrowing of our heart valves. If you have a family history of early heart disease and high cholesterol, you should check your entire family for Familial Hypercholesterolemia (FH). [youtube.com]

• Seizure

  Plus, Type 1 5 Generalized Epilepsy With Febrile Seizures Plus, Type 2 3 Generalized Epilepsy With Febrile Seizures Plus, Type 3 5 Generalized Epilepsy With Febrile Seizures Plus, Type 7 5 Generalized Epilepsy with Febrile Seizures Plus, Type 9 3 Genitopatellar [preventiongenetics.com]

  Less common clinical features include intestinal bleeding, pallor, anemia, irritability, diarrhea, seizures and encephalopathy [ 10, 11 ]. [mdpi.com]

Clinical findings should raise suspicion of hypercholesterolemia. This suspicion may be supported by information as to the medical condition of the patient's parents and grandparents: Since FCH is inherited in an autosomal dominant pattern, there may be reports about elevated blood fat levels, xanthomas, and cardiovascular disorders.

In any case, standard analyses of blood samples reveal elevated levels of total cholesterol and LDL. As a rule of thumb, LDL concentrations are about four and two times increased in individuals with homozygous and heterozygous FCH, respectively, when compared to healthy relatives [4]. The specific threshold concentrations of lipids depend on the age of the patient and their family history [5], and it may not always be possible to confirm or refute the tentative diagnosis on the basis of laboratory results.

A more reliable diagnosis of FCH is based on the identification of the underlying mutation of the LDLR gene [6]. In this context, straight-forward analyses may be carried out if the parents' genotype is known. Otherwise, LDLR gene sequencing is required. Genes APOB and PCSK9 may be assessed if LDLR mutations are not detected, but despite all efforts, the molecular biological confirmation of FCH is not universally achieved. For homozygous FCH, the following criteria may then be applied to make a clinical diagnosis [4]:

• Untreated LDL levels of >13 mmol/l or 500 mg/dl, or treated LDL levels of >8 mmol/l or 300 mg/dl, and
• Untreated LDL levels consistent with heterozygous FCH in both parents, or cutaneous or tendon xanthomas before the age 10 years

Patients who have been diagnosed with FCH should undergo regular screenings for aortic and coronary heart disease [4].

• Nephrolithiasis

  CONCLUSIONS Acute renal infarction is often missed or delayed as a diagnosis because patients often present with flank pain that can resemble more frequently encountered conditions such as pyelonephritis and nephrolithiasis. [ncbi.nlm.nih.gov]

  Calcium Oxalate 2 Nephrolithiasis/Osteoporosis, Hypophosphatemic, 1 1 Nephrolithiasis/Osteoporosis, Hypophosphatemic, 2 2 Nephronophthisis 3 Nephronophthisis 11 3 Nephronophthisis 12 3 Nephronophthisis 13 2 Nephronophthisis 14 1 Nephronophthisis 15 [preventiongenetics.com]

  […] intervention group for a difference of 14.0% ( P Of 421 patients assigned to surgery, 22 refused to undergo the operation and 23 underwent reversal of the partial ileal bypass procedure up to July 1990, primarily for intolerable diarrhea or recurrent nephrolithiasis [doi.org]

• Hypercholesterolemia

  Clinical findings should raise suspicion of hypercholesterolemia. [symptoma.com]

  1 If a child with familial hypercholesterolemia is identified, the parent with familial hypercholesterolemia may then be identified. [doi.org]

  CONCLUSIONS: Nonfamilial hypercholesterolemia genetic hypercholesterolemia families concentrate risk alleles for high LDL-C. [ncbi.nlm.nih.gov]

• Hypertriglyceridemia

  […] and/or fenofibrate type 5 mixed hypertriglyceridemia Increased production or decreased clearance of VLDL and chylomicrons. [quizlet.com]

  Hyperlipidemias are also classified according to which types of lipids are elevated, that is hypercholesterolemia, hypertriglyceridemia or both in combined hyperlipidemia. [en.wikipedia.org]

  Hubacek JA et al. (2005) Hypertriglyceridemia: interaction between APOE and APOAV variants. Clin Chem 51 : 1311–1313 39. [nature.com]

  Managing hypertriglyceridemia in special situations. Table 6. Managing hypertriglyceridemia in special situations. [mdpi.com]

  familial combined hyperlipidemia, sporadic hypertriglyceridemia, diabetes N+ ++ V Creamy top, turbid bottom Chylomicrons, VLDL Diabetes + ++ Note that the WHO classification is simply a biochemical phenotypic classification based on which lipoprotein [gpnotebook.co.uk]

Cholesterol-lowering drug therapy is the mainstay of treatment and should be initiated as early as possible. In this context, statins, ezetimibe, and bile acid sequestrants are most commonly prescribed. The patients' response to therapy varies largely and cannot be predicted based on the results of genetic studies [6] [7]. If LDL target levels cannot be achieved, weekly or biweekly adjunctive lipoprotein apheresis is recommended. The following target levels have been defined by the European Atherosclerosis Society [6]:

• LDL <3.5 mmol/l or <135 mg/dl in children
• LDL <2.5 mmol/l or <100 mg/dl in adults
• LDL <1.8 mmol/l or <70 mg/dl in adults with atheroscleroslerotic cardiovascular disease and/or diabetes mellitus

These values apply to both homozygous and heterozygous FCH.

In any case, medical therapy should be complemented by lifestyle adjustments. Patients are to receive dietary counseling and should be advised on how to reduce the intake of exogenous cholesterol and saturated fats [1]. Regular, moderate exercise is recommended if cardiovascular findings don't suggest an imminent risk of angina pectoris upon exertion [4]. FCH patients should be discouraged from smoking [6].

Since FCH is associated with an elevated risk to develop coronary heart disease and other life-threatening cardiovascular disorders, the early diagnosis and appropriate management of the disease is essential for obtaining a favorable outcome [3] [8]. If left untreated, homozygous FCH is generally fatal before the age of 30 years [4]. Those suffering from heterozygous FCH have a 5%, 20% and 50% risk of coronary artery disease at ages 30, 40 and 50 years, respectively [1]. The adequate treatment of FCH is assumed to increase the patients' life expectancy by several decades [9].

FCH is caused by mutations of the LDLR gene. This gene is located on the short arm of chromosome 19 and encodes for the LDL receptor, which mediates the uptake of LDL. The life cycle of the LDL receptor comprises LDL binding, the formation and internalization of endocytic vesicles, the dissociation from these vesicles, and the return to the cell surface. Either of these processes may be impaired in FCH patients, and pathogenic mutations of LDLR are thus classified into distinct groups [7] [9]:

• Defective intracellular transport
• Defective ligand binding
• Defective internalization
• Defective recycling
• Null mutations resulting in no detectable protein

More than 1,200 mutations of LDLR have been described to date [6]. Certain genotype-phenotype correlations could be established: In patients suffering from homozygous FCH, the residual activity of the LDL receptor correlates with the severity of the disease. Somewhat surprisingly though, LDL receptor activity is unsuited to predict the course of the disease in heterozygous individuals. In general, genetic modulators and environmental factors seem to considerably affect the outcome. Those who are exposed to cigarette smoke are at increased risks of cardiovascular disorders, as are those suffering from diabetes mellitus, males and elder patients [7] [9].

The prevalence of heterozygous FCH has been estimated at 1 in 500 persons. Accordingly, the frequency of homozygous FCH may approximate 1 in 1,000,000 inhabitants [4] [7]. Particularly high prevalence rates due to founder effects have been described for Christian Lebanese, French Canadians, and South African Afrikaners, among others [9]. Males and females are affected equally.

Literature contains contradictory data regarding the penetrance of LDLR mutations. Some experts state the penetrance to be almost 100%, while others describe considerable shares of normocholesterolemic carriers in affected families [9] [10]. It has been speculated that the existence of protective factors and cholesterol-lowering gene variants may account for this phenomenon, but evidence has yet to be provided [10].

LDL consist of apolipoprotein B-100 and other proteins, of triglycerides, phospholipids, cholesteryl esters, and free cholesterol. They are remnants of very-low-density lipoproteins (VLDL) that have delivered triglycerides to peripheral tissues, where they are used as energy substrates. Accordingly, the relative contents of cholesterol and cholesteryl esters increase when VLDL convert to LDL. Cells in need of either lipid enhance the expression of LDL receptors, which are able to bind and internalize circulating LDL. In this context, hepatocytes remove the major portion of LDL from the circulation. After their uptake into cells, LDL are disassembled: Proteins are lysosomally degraded, cholesterol esters are hydrolyzed, and cholesterol is made available for the inhibition of 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMG-CoA reductase), the rate-limiting enzyme in cholesterol synthesis.

In patients carrying loss-of-function mutations of the LDLR gene, clearing LDL from blood is largely impaired. The regulatory mechanism described above is overridden, and HMG-CoA reductase continues to provide mevalonate for the synthesis of cholesterol. Both conditions contribute to the elevation of blood levels of LDL [7]. Excess lipids are eventually deposited in the cornea, skin, tendons, and arteries. The accumulation of foam cells in the intima of arteries may rapidly progress to occlusive atherosclerosis, plaque formation, coronary ostial stenosis, and myocardial infarction [1].

Due to the high prevalence of FCH and the clear benefits of an early diagnosis and initiation of therapy, population screenings have repeatedly been considered. The genetic heterogeneity of FCH, patients, however, imposes severe practical limitations on this proposition. The screening of families known to harbor pathogenic mutations of the LDLR gene is the better approach: It is more cost-effective and may involve straight-forward analyses for those mutations detected in the index case [7].

The prenatal diagnosis of FCH is feasible if the parents' genotype has been determined.

Owing to its specific features, FCH is considered both a type of autosomal dominant hypercholesterolemia and primary hyperlipidemia. The corresponding classification systems shall be briefly summarized in this paragraph to dispel doubts as to the nomenclature, which may be confusing.

Hyperlipidemias are divided into categories according to the Fredrickson classification [11]. There are six types of primary hyperlipidemias:

• Type 1: Familial chylomicronemia or hyperlipoproteinemia type 1
• Type 2A: FCH or hyperlipoproteinemia type 2, as described here
• Type 2B: Familial combined hyperlipidemia
• Type 3: Familial dysbetalipoproteinemia or hyperlipoproteinemia type 3
• Type 4: Familial hypertriglyceridemia
• Type 5: Primary mixed hyperlipidemia

Contrary to the other types of primary hyperlipidemia, FCH is not associated with increased levels of triglycerides, but with pure hypercholesterolemia. More than 80 genes have been shown to affect cholesterol levels, and pathogenic mutations of those genes may result in increased levels of cholesterol [8]. Distinct types of hypercholesterolemia may be classified according to the underlying gene defects, the pattern of inheritance, the clinical presentation, or biochemical findings such as the elevated lipoprotein fraction. Because the vast majority of cases may be attributed to mutations of genes LDLR, APOB, and PCSK9, they provide the basis of current classification systems [8]:

• FCH or hyperlipoproteinemia type 2, as discussed in this article, is primarily caused by LDLR mutations.
• Mutations of the APOB gene may result in hypercholesterolemia type B. This disease is also referred to as familial defective apolipoprotein B-100.
• Finally, PCSK9 mutations may lead to autosomal dominant hypercholesterolemia type 3.

As implied above, a minor share of patients diagnosed with autosomal dominant hypercholesterolemia tests negative for any of the aforementioned mutations. Even though mutations may be detected that predispose for hypercholesterolemia, such as anomalies of genes GSBS and ITIH4, these are not usually considered sufficient to induce the disease. The true causes of these cases remain unknown, and they are not covered by the current classification scheme. The need for revision will eventually arise, as the molecular biological background and the pathogenesis of hypercholesterolemia are increasingly better understood.

Hyperlipoproteinemia type 2 is also referred to as familial hypercholesterolemia. It is a hereditary disorder of cholesterol metabolism, and affected individuals present increased levels of total cholesterol and low-density lipoproteins (LDL), whereby LDL are commonly described as "bad cholesterol". Eventually, excess blood fats are deposited in the cornea, skin, tendons, and arteries. The formation of plaques in the arterial walls is least visible but most detrimental; it leads to atherosclerosis and may trigger coronary heart disease and myocardial infarction.

Familial hypercholesterolemia is caused by mutations in the gene encoding for the LDL receptor. About 1 in 500 people has inherited such a mutation from one of their parents and is heterozygous for the pathogenic allele. Homozygosity, i.e., the inheritance of two defective alleles from both parents, occurs about once in a million births. Symptom onset in childhood and severe atherosclerosis by the end of the second decade of life are characteristic of homozygous familial hypercholesterolemia, but in heterozygous individuals, the risk of cardiovascular complications is far from negligible either: By the age of 50 years, 50% of patients have been diagnosed with coronary artery disease.

Although the deposition of blood fats in the arteries does not imply obvious complaints, it should be taken seriously. The life expectancy of people carrying defective LDL receptors largely depends on the early diagnosis and appropriate management of the disease.

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