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Familial hypercholesterolemia(FH)

MedGen UID:
5688
Concept ID:
C0020445
Disease or Syndrome
Synonyms: FH; Fredrickson type IIa hyperlipoproteinemia; Hyper-beta-lipoproteinemia; HYPER-LOW-DENSITY-LIPOPROTEINEMIA; HYPERCHOLESTEROLEMIA, FAMILIAL, MODIFIER OF; HYPERCHOLESTEROLEMIC XANTHOMATOSIS, FAMILIAL; Hyperlipoproteinemia type 2; Hyperlipoproteinemia Type II; Hyperlipoproteinemia Type IIa; LDL RECEPTOR DISORDER; LDLR-Related Familial Hypercholesterolemia, Autosomal Dominant
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Source: HPO
Autosomal dominant inheritance refers to genetic conditions that occur when a mutation is present in one copy of a given gene (i.e., the person is heterozygous).
SNOMED CT: Familial hypercholesterolemia (398036000); Essential familial hypercholesterolemia (398036000); Familial hyperbetalipoproteinemia (398036000); LDL receptor disorder (398036000); LDL - Low density lipoprotein receptor disorder (398036000); Low density lipoprotein catabolic defect (398036000); Hyperbetalipoproteinemia (190773008)
 
Genes (locations): ABCA1 (9q31.1); APOA2 (1q23.3); EPHX2 (8p21.2-21.1); GHR (5p13.1-12); ITIH4 (3p21.1); LDLR (19p13.2); PPP1R17 (7p14.3)
OMIM®: 143890; 144400

Definition

Familial hypercholesterolemia is an autosomal dominant disorder characterized by elevation of serum cholesterol bound to low density lipoprotein (LDL), which promotes deposition of cholesterol in the skin (xanthelasma), tendons (xanthomas), and coronary arteries (atherosclerosis). The disorder occurs in 2 clinical forms: homozygous and heterozygous (summary by Hobbs et al., 1992). [from OMIM]

Additional description

From GHR
Hypercholesterolemia is a condition characterized by very high levels of cholesterol in the blood. Cholesterol is a waxy, fat-like substance that is produced in the body and obtained from foods that come from animals (particularly egg yolks, meat, poultry, fish, and dairy products). The body needs this substance to build cell membranes, make certain hormones, and produce compounds that aid in fat digestion. Too much cholesterol, however, increases a person's risk of developing heart disease.People with hypercholesterolemia have a high risk of developing a form of heart disease called coronary artery disease. This condition occurs when excess cholesterol in the bloodstream is deposited in the walls of blood vessels, particularly in the arteries that supply blood to the heart (coronary arteries). The abnormal buildup of cholesterol forms clumps (plaque) that narrow and harden artery walls. As the clumps get bigger, they can clog the arteries and restrict the flow of blood to the heart. The buildup of plaque in coronary arteries causes a form of chest pain called angina and greatly increases a person's risk of having a heart attack.Inherited forms of hypercholesterolemia can also cause health problems related to the buildup of excess cholesterol in other tissues. If cholesterol accumulates in tendons, it causes characteristic growths called tendon xanthomas. These growths most often affect the Achilles tendons and tendons in the hands and fingers. Yellowish cholesterol deposits under the skin of the eyelids are known as xanthelasmata. Cholesterol can also accumulate at the edges of the clear, front surface of the eye (the cornea), leading to a gray-colored ring called an arcus cornealis.  http://ghr.nlm.nih.gov/condition/hypercholesterolemia

Clinical features

Atherosclerosis
MedGen UID:
13948
Concept ID:
C0004153
Disease or Syndrome
Atherosclerosis is a disease in which plaque builds up inside your arteries. Plaque is a sticky substance made up of fat, cholesterol, calcium, and other substances found in the blood. Over time, plaque hardens and narrows your arteries. That limits the flow of oxygen-rich blood to your body. Atherosclerosis can lead to serious problems, including. -Coronary artery disease. These arteries supply blood to your heart. When they are blocked, you can suffer angina or a heart attack. -Carotid artery disease. These arteries supply blood to your brain. When they are blocked you can suffer a stroke. -Peripheral arterial disease. These arteries are in your arms, legs and pelvis. When they are blocked, you can suffer from numbness, pain and sometimes infections. Atherosclerosis usually doesn't cause symptoms until it severely narrows or totally blocks an artery. Many people don't know they have it until they have a medical emergency. A physical exam, imaging, and other diagnostic tests can tell if you have it. Medicines can slow the progress of plaque buildup. Your doctor may also recommend procedures such as angioplasty to open the arteries, or surgery on the coronary or carotid arteries. Lifestyle changes can also help. These include following a healthy diet, getting regular exercise, maintaining a healthy weight, quitting smoking, and managing stress. . NIH: National Heart, Lung, and Blood Institute.
Arcus corneae
MedGen UID:
8179
Concept ID:
C0003742
Finding
A hazy, grayish-white ring about 2 mm in width located close to but separated from the limbus (the corneoscleral junction). Corneal arcus generally occurs bilaterally, and is related to lipid deposition in the cornea. Corneal arcus can occur in elderly persons as a part of the aging process but may be associated with hypercholesterolemia in people under the age of 50 years.
Hypercholesterolaemia
MedGen UID:
5687
Concept ID:
C0020443
Disease or Syndrome
An increased concentration of cholesterol in the blood.
Familial hypercholesterolemia
MedGen UID:
5688
Concept ID:
C0020445
Disease or Syndrome
Familial hypercholesterolemia is an autosomal dominant disorder characterized by elevation of serum cholesterol bound to low density lipoprotein (LDL), which promotes deposition of cholesterol in the skin (xanthelasma), tendons (xanthomas), and coronary arteries (atherosclerosis). The disorder occurs in 2 clinical forms: homozygous and heterozygous (summary by Hobbs et al., 1992).
Hypertriglyceridemia
MedGen UID:
279403
Concept ID:
C1522137
Finding
An abnormal increase in the level of triglycerides in the blood.
Xanthelasma
MedGen UID:
56357
Concept ID:
C0155210
Disease or Syndrome
The presence of xanthomata in the skin of the eyelid.
Abnormality of the skin
MedGen UID:
11449
Concept ID:
C0037268
Finding
An abnormality of the skin.
Xanthelasma
MedGen UID:
56357
Concept ID:
C0155210
Disease or Syndrome
The presence of xanthomata in the skin of the eyelid.

Term Hierarchy

Conditions with this feature

Familial hypercholesterolemia
MedGen UID:
5688
Concept ID:
C0020445
Disease or Syndrome
Familial hypercholesterolemia is an autosomal dominant disorder characterized by elevation of serum cholesterol bound to low density lipoprotein (LDL), which promotes deposition of cholesterol in the skin (xanthelasma), tendons (xanthomas), and coronary arteries (atherosclerosis). The disorder occurs in 2 clinical forms: homozygous and heterozygous (summary by Hobbs et al., 1992).
Niemann-Pick disease, type B
MedGen UID:
78651
Concept ID:
C0268243
Disease or Syndrome
Acid sphingomyelinase (ASM) deficiency has been categorized in the past as either neuronopathic (Niemann-Pick disease type A [NPD-A]), with death in early childhood, or non-neuronopathic (Niemann-Pick disease type B [NPD-B]). While forms intermediate to these two extremes occur, all ASM deficiency that is not NPD-A is designated in this review as NPD-B, despite its wide range of manifestations and severity. The first symptom in NPD-A is hepatosplenomegaly, usually noted by age three months; over time the liver and spleen become massive. Psychomotor development progresses no further than the 12-month level, after which neurologic deterioration is relentless. A classic cherry-red spot of the macula of the retina, which may not be present in the first few months, is eventually present in all affected children. Interstitial lung disease caused by storage of sphingomyelin in pulmonary macrophages results in frequent respiratory infections and often respiratory failure. Most children succumb before the third year. NPD type B, later in onset and milder in manifestations than NPD type A, is characterized by hepatosplenomegaly with progressive hypersplenism and stable liver dysfunction, gradual deterioration in pulmonary function, osteopenia, and atherogenic lipid profile. Progressive and/or clinically significant neurologic manifestations occur infrequently. Survival to adulthood can occur.
Familial hemophagocytic lymphohistiocytosis
MedGen UID:
78797
Concept ID:
C0272199
Pathologic Function
Familial hemophagocytic lymphohistiocytosis (FHL) is characterized by proliferation and infiltration of hyperactivated macrophages and T-lymphocytes manifesting as acute illness with prolonged fever, cytopenias, and hepatosplenomegaly. Onset is typically within the first months or years of life and, on occasion, in utero, although later childhood or adult onset is more common than previously suspected. Neurologic abnormalities may be present initially or may develop later; they may include increased intracranial pressure, irritability, neck stiffness, hypotonia, hypertonia, convulsions, cranial nerve palsies, ataxia, hemiplegia, quadriplegia, blindness, and coma. Rash and lymphadenopathy are less common. Other findings include liver dysfunction and bone marrow hemophagocytosis. The median survival of children with typical FHL, without treatment, is less than two months; progression of hemophagocytic lymphohistiocytosis and infection account for the majority of deaths in untreated individuals.
Fish-eye disease
MedGen UID:
83354
Concept ID:
C0342895
Disease or Syndrome
Fish-eye disease, also called partial LCAT deficiency, is a disorder that causes the clear front surface of the eyes (the corneas) to gradually become cloudy. The cloudiness, which generally first appears in adolescence or early adulthood, consists of small grayish dots of cholesterol (opacities) distributed across the corneas. Cholesterol is a waxy, fat-like substance that is produced in the body and obtained from foods that come from animals; it aids in many functions of the body but can become harmful in excessive amounts. As fish-eye disease progresses, the corneal cloudiness worsens and can lead to severely impaired vision.
Hyperlipoproteinemia, type II, and deafness
MedGen UID:
326732
Concept ID:
C1840425
Disease or Syndrome
Ataxia with vitamin E deficiency
MedGen UID:
341248
Concept ID:
C1848533
Disease or Syndrome
Most individuals with ataxia with vitamin E deficiency (AVED) present at puberty; common characteristics of the disease include progressive ataxia, clumsiness of the hands, loss of proprioception (especially of vibration and joint position sense), and areflexia. Other features often observed are dysdiadochokinesia, positive Romberg sign, head titubation, decreased visual acuity, and positive Babinski sign. The phenotype and disease severity vary widely among families with different mutations; age of onset and disease course are more uniform within a given family, but symptoms and disease severity can vary even among sibs.
Morbid obesity and spermatogenic failure
MedGen UID:
816654
Concept ID:
C3810324
Disease or Syndrome

Professional guidelines

PubMed

Feldman DI, Blaha MJ, Santos RD, Jones SR, Blumenthal RS, Toth PP, Sperling LS, Martin SS
Curr Atheroscler Rep 2015 Jan;17(1):473. doi: 10.1007/s11883-014-0473-6. PMID: 25404096
ACMG Board of Directors
Genet Med 2015 Jan;17(1):68-9. Epub 2014 Nov 13 doi: 10.1038/gim.2014.151. [Epub ahead of print] PMID: 25356965
Cuchel M, Bruckert E, Ginsberg HN, Raal FJ, Santos RD, Hegele RA, Kuivenhoven JA, Nordestgaard BG, Descamps OS, Steinhagen-Thiessen E, Tybjærg-Hansen A, Watts GF, Averna M, Boileau C, Borén J, Catapano AL, Defesche JC, Hovingh GK, Humphries SE, Kovanen PT, Masana L, Pajukanta P, Parhofer KG, Ray KK, Stalenhoef AF, Stroes E, Taskinen MR, Wiegman A, Wiklund O, Chapman MJ; European Atherosclerosis Society Consensus Panel on Familial Hypercholesterolaemia
Eur Heart J 2014 Aug 21;35(32):2146-57. Epub 2014 Jul 22 doi: 10.1093/eurheartj/ehu274. [Epub ahead of print] PMID: 25053660Free PMC Article
Myśliwiec M, Walczak M, Małecka-Tendera E, Dobrzańska A, Cybulska B, Filipiak K, Mazur A, Jarosz-Chobot P, Szadkowska A, Rynkiewicz A, Chybicka A, Socha P, Brandt A, Bautembach-Minkowska J, Zdrojewski T, Limon J, Gidding SS, Banach M
J Clin Lipidol 2014 Mar-Apr;8(2):173-80. Epub 2014 Jan 18 doi: 10.1016/j.jacl.2014.01.001. [Epub ahead of print] PMID: 24636176
Watts GF, Gidding S, Wierzbicki AS, Toth PP, Alonso R, Brown WV, Bruckert E, Defesche J, Lin KK, Livingston M, Mata P, Parhofer KG, Raal FJ, Santos RD, Sijbrands EJ, Simpson WG, Sullivan DR, Susekov AV, Tomlinson B, Wiegman A, Yamashita S, Kastelein JJ
Int J Cardiol 2014 Feb 15;171(3):309-25. Epub 2013 Nov 20 doi: 10.1016/j.ijcard.2013.11.025. [Epub ahead of print] PMID: 24418289
Green RC, Berg JS, Grody WW, Kalia SS, Korf BR, Martin CL, McGuire AL, Nussbaum RL, O'Daniel JM, Ormond KE, Rehm HL, Watson MS, Williams MS, Biesecker LG; American College of Medical Genetics and Genomics
Genet Med 2013 Jul;15(7):565-74. Epub 2013 Jun 20 doi: 10.1038/gim.2013.73. [Epub ahead of print] PMID: 23788249Free PMC Article
Rynkiewicz A, Cybulska B, Banach M, Filipiak K, Guzik T, Idzior-Waluś B, Imiela J, Jankowski P, Kłosiewicz-Latoszek L, Limon J, Myśliwiec M, Opolski G, Steciwko A, Stępińska J, Zdrojewski T
J Clin Lipidol 2013 May-Jun;7(3):217-21. Epub 2013 Feb 4 doi: 10.1016/j.jacl.2013.01.005. [Epub ahead of print] PMID: 23725921
Sullivan DR, Hamilton-Craig I, van Bockxmeer F, Watts GF; CSANZ Cardiac Genetics Diseases Council Writing Group
Heart Lung Circ 2012 Mar;21(3):159-62. Epub 2012 Jan 30 doi: 10.1016/j.hlc.2011.11.006. [Epub ahead of print] PMID: 22364837
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
J Clin Lipidol 2011 Jun;5(3 Suppl):S1-8. Epub 2011 Apr 12 doi: 10.1016/j.jacl.2011.04.003. [Epub ahead of print] PMID: 21600525
Civeira F; International Panel on Management of Familial Hypercholesterolemia
Atherosclerosis 2004 Mar;173(1):55-68. doi: 10.1016/j.atherosclerosis.2003.11.010. PMID: 15177124

External

Identification and management of familial hypercholesterolaemia

Recent clinical studies

Etiology

ten Kate GJ, Bos S, Dedic A, Neefjes LA, Kurata A, Langendonk JG, Liem A, Moelker A, Krestin GP, de Feyter PJ, Roeters van Lennep JE, Nieman K, Sijbrands EJ
J Am Coll Cardiol 2015 Dec 22;66(24):2687-95. doi: 10.1016/j.jacc.2015.09.087. PMID: 26700830
Pereira C, Miname MH, Makdisse MR, Watanabe C, Pesaro AE, Jannes CE, Kalil Filho R, Pereira AC, Santos RD
Atherosclerosis 2015 Sep;242(1):174-8. Epub 2015 Jul 13 doi: 10.1016/j.atherosclerosis.2015.07.022. [Epub ahead of print] PMID: 26201001
Besseling J, Kastelein JJ, Defesche JC, Hutten BA, Hovingh GK
JAMA 2015 Mar 10;313(10):1029-36. doi: 10.1001/jama.2015.1206. PMID: 25756439
Vuorio A, Kuoppala J, Kovanen PT, Humphries SE, Tonstad S, Wiegman A, Drogari E
Cochrane Database Syst Rev 2014 Jul 23;(7):CD006401. doi: 10.1002/14651858.CD006401.pub3. PMID: 25054950
Santos RD, Maranhao RC
Curr Opin Lipidol 2014 Jun;25(3):183-8. doi: 10.1097/MOL.0000000000000073. PMID: 24699416

Diagnosis

Icli A, Aksoy F, Nar G, Kaymaz H, Alpay MF, Nar R, Guclu A, Arslan A, Dogan A
Angiology 2016 Feb;67(2):146-50. Epub 2015 Apr 9 doi: 10.1177/0003319715579781. [Epub ahead of print] PMID: 25859052
ten Kate GJ, Bos S, Dedic A, Neefjes LA, Kurata A, Langendonk JG, Liem A, Moelker A, Krestin GP, de Feyter PJ, Roeters van Lennep JE, Nieman K, Sijbrands EJ
J Am Coll Cardiol 2015 Dec 22;66(24):2687-95. doi: 10.1016/j.jacc.2015.09.087. PMID: 26700830
Pereira C, Miname MH, Makdisse MR, Watanabe C, Pesaro AE, Jannes CE, Kalil Filho R, Pereira AC, Santos RD
Atherosclerosis 2015 Sep;242(1):174-8. Epub 2015 Jul 13 doi: 10.1016/j.atherosclerosis.2015.07.022. [Epub ahead of print] PMID: 26201001
Vuorio A, Kuoppala J, Kovanen PT, Humphries SE, Tonstad S, Wiegman A, Drogari E
Cochrane Database Syst Rev 2014 Jul 23;(7):CD006401. doi: 10.1002/14651858.CD006401.pub3. PMID: 25054950
Santos RD, Maranhao RC
Curr Opin Lipidol 2014 Jun;25(3):183-8. doi: 10.1097/MOL.0000000000000073. PMID: 24699416

Therapy

Pereira C, Miname MH, Makdisse MR, Watanabe C, Pesaro AE, Jannes CE, Kalil Filho R, Pereira AC, Santos RD
Atherosclerosis 2015 Sep;242(1):174-8. Epub 2015 Jul 13 doi: 10.1016/j.atherosclerosis.2015.07.022. [Epub ahead of print] PMID: 26201001
Bouhairie VE, Goldberg AC
Cardiol Clin 2015 May;33(2):169-79. doi: 10.1016/j.ccl.2015.01.001. PMID: 25939291Free PMC Article
Kolovou G, Vasiliadis I, Gontoras N, Kolovou V, Hatzigeorgiou G
Cardiovasc Ther 2015 Apr;33(2):71-8. doi: 10.1111/1755-5922.12105. PMID: 25604780
Hiddink L, Dallinga-Thie GM, Hovingh GK, de Visser MC, Peer PG, Stalenhoef AF, van Heerde WL
Atherosclerosis 2015 Feb;238(2):195-200. Epub 2014 Nov 29 doi: 10.1016/j.atherosclerosis.2014.11.023. [Epub ahead of print] PMID: 25525746
Vuorio A, Kuoppala J, Kovanen PT, Humphries SE, Tonstad S, Wiegman A, Drogari E
Cochrane Database Syst Rev 2014 Jul 23;(7):CD006401. doi: 10.1002/14651858.CD006401.pub3. PMID: 25054950

Prognosis

Icli A, Aksoy F, Nar G, Kaymaz H, Alpay MF, Nar R, Guclu A, Arslan A, Dogan A
Angiology 2016 Feb;67(2):146-50. Epub 2015 Apr 9 doi: 10.1177/0003319715579781. [Epub ahead of print] PMID: 25859052
ten Kate GJ, Bos S, Dedic A, Neefjes LA, Kurata A, Langendonk JG, Liem A, Moelker A, Krestin GP, de Feyter PJ, Roeters van Lennep JE, Nieman K, Sijbrands EJ
J Am Coll Cardiol 2015 Dec 22;66(24):2687-95. doi: 10.1016/j.jacc.2015.09.087. PMID: 26700830
Bos S, Duvekot MH, Touw-Blommesteijn AC, Verhoeven AJ, Mulder MT, Watts GF, Sijbrands EJ, Roeters van Lennep JE
Atherosclerosis 2015 Sep;242(1):226-9. Epub 2015 Jul 14 doi: 10.1016/j.atherosclerosis.2015.07.024. [Epub ahead of print] PMID: 26222903
Pereira C, Miname MH, Makdisse MR, Watanabe C, Pesaro AE, Jannes CE, Kalil Filho R, Pereira AC, Santos RD
Atherosclerosis 2015 Sep;242(1):174-8. Epub 2015 Jul 13 doi: 10.1016/j.atherosclerosis.2015.07.022. [Epub ahead of print] PMID: 26201001
Hiddink L, Dallinga-Thie GM, Hovingh GK, de Visser MC, Peer PG, Stalenhoef AF, van Heerde WL
Atherosclerosis 2015 Feb;238(2):195-200. Epub 2014 Nov 29 doi: 10.1016/j.atherosclerosis.2014.11.023. [Epub ahead of print] PMID: 25525746

Clinical prediction guides

Icli A, Aksoy F, Nar G, Kaymaz H, Alpay MF, Nar R, Guclu A, Arslan A, Dogan A
Angiology 2016 Feb;67(2):146-50. Epub 2015 Apr 9 doi: 10.1177/0003319715579781. [Epub ahead of print] PMID: 25859052
ten Kate GJ, Bos S, Dedic A, Neefjes LA, Kurata A, Langendonk JG, Liem A, Moelker A, Krestin GP, de Feyter PJ, Roeters van Lennep JE, Nieman K, Sijbrands EJ
J Am Coll Cardiol 2015 Dec 22;66(24):2687-95. doi: 10.1016/j.jacc.2015.09.087. PMID: 26700830
Pereira C, Miname MH, Makdisse MR, Watanabe C, Pesaro AE, Jannes CE, Kalil Filho R, Pereira AC, Santos RD
Atherosclerosis 2015 Sep;242(1):174-8. Epub 2015 Jul 13 doi: 10.1016/j.atherosclerosis.2015.07.022. [Epub ahead of print] PMID: 26201001
Kwon M, Han SM, Kim DI, Rhee MY, Lee BK, Ahn YK, Cho BR, Woo J, Hur SH, Jeong JO, Jang Y, Lee SH, Lee JH
Atherosclerosis 2015 Sep;242(1):8-12. Epub 2015 Jun 30 doi: 10.1016/j.atherosclerosis.2015.06.053. [Epub ahead of print] PMID: 26160041
Hiddink L, Dallinga-Thie GM, Hovingh GK, de Visser MC, Peer PG, Stalenhoef AF, van Heerde WL
Atherosclerosis 2015 Feb;238(2):195-200. Epub 2014 Nov 29 doi: 10.1016/j.atherosclerosis.2014.11.023. [Epub ahead of print] PMID: 25525746

Recent systematic reviews

Bamimore MA, Zaid A, Banerjee Y, Al-Sarraf A, Abifadel M, Seidah NG, Al-Waili K, Al-Rasadi K, Awan Z
J Clin Lipidol 2015 Mar-Apr;9(2):187-94. Epub 2014 Nov 29 doi: 10.1016/j.jacl.2014.11.008. [Epub ahead of print] PMID: 25911074
Brautbar A, Leary E, Rasmussen K, Wilson DP, Steiner RD, Virani S
Curr Atheroscler Rep 2015 Apr;17(4):491. doi: 10.1007/s11883-015-0491-z. PMID: 25712136
Ademi Z, Watts GF, Pang J, Sijbrands EJ, van Bockxmeer FM, O'Leary P, Geelhoed E, Liew D
J Clin Lipidol 2014 Jul-Aug;8(4):390-400. Epub 2014 Jun 12 doi: 10.1016/j.jacl.2014.05.008. [Epub ahead of print] PMID: 25110220
Vuorio A, Kuoppala J, Kovanen PT, Humphries SE, Tonstad S, Wiegman A, Drogari E
Cochrane Database Syst Rev 2014 Jul 23;(7):CD006401. doi: 10.1002/14651858.CD006401.pub3. PMID: 25054950
Narverud I, Retterstøl K, Iversen PO, Halvorsen B, Ueland T, Ulven SM, Ose L, Aukrust P, Veierød MB, Holven KB
Atherosclerosis 2014 Aug;235(2):299-309. Epub 2014 May 20 doi: 10.1016/j.atherosclerosis.2014.05.917. [Epub ahead of print] PMID: 24908240

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