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Hypercholesterolemia, familial, 4(FHCL4)

MedGen UID:
400313
Concept ID:
C1863512
Disease or Syndrome
Synonyms: Familial Hypercholesterolemia, Autosomal Recessive; FHCL4; Hypercholesterolemia, autosomal recessive; HYPERCHOLESTEROLEMIA, AUTOSOMAL RECESSIVE, 1; HYPERCHOLESTEROLEMIA, AUTOSOMAL RECESSIVE, 2
 
Gene (location): LDLRAP1 (1p36.11)
 
Monarch Initiative: MONDO:0011374
OMIM®: 603813

Disease characteristics

Excerpted from the GeneReview: Familial Hypercholesterolemia
Familial hypercholesterolemia (FH) is characterized by significantly elevated low-density lipoprotein cholesterol (LDL-C) that leads to atherosclerotic plaque deposition in the coronary arteries and proximal aorta at an early age and increases the risk of premature cardiovascular events such as angina and myocardial infarction; stroke occurs more rarely. Xanthomas (cholesterol deposits in tendons) may be visible in the Achilles tendons or tendons of the hands and worsen with age as a result of extremely high cholesterol levels. Xanthelasmas (yellowish, waxy deposits) can occur around the eyelids. Individuals with FH may develop corneal arcus (white, gray, or blue opaque ring in the corneal margin as a result of cholesterol deposition) at a younger age than those without FH. Individuals with a more severe phenotype, often as a result of biallelic variants, can present with very significant elevations in LDL-C (>500 mg/dL), early-onset coronary artery disease (CAD; presenting as early as childhood in some), and calcific aortic valve disease. [from GeneReviews]
Authors:
Hannah E Ison  |  Shoa L Clarke  |  Joshua W Knowles   view full author information

Additional descriptions

From OMIM
Autosomal recessive familial hypercholesterolemia-4 (FCHL4) is a rare monogenic disease characterized by very high levels of low-density lipoprotein (LDL) cholesterol (usually above 400 mg/dl) and increased risk of premature atherosclerotic cardiovascular disease (summary by Sanchez-Hernandez et al., 2018).  http://www.omim.org/entry/603813
From MedlinePlus Genetics
Familial hypercholesterolemia is an inherited 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. In people with familial hypercholesterolemia, the body is unable to get rid of extra cholesterol, and it builds up in the blood. Too much cholesterol increases a person's risk of developing heart disease.

Familial hypercholesterolemia can also cause health problems related to the buildup of excess cholesterol in tissues other than the heart and blood vessels. If cholesterol accumulates in the tissues that attach muscles to bones (tendons), it causes characteristic growths called tendon xanthomas. These growths most often affect the Achilles tendons, which attach the calf muscles to the heels, and tendons in the hands and fingers. Yellowish cholesterol deposits can develop under the skin of the eyelids and 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.

People with familial hypercholesterolemia have a high risk of developing a form of heart disease called coronary artery disease at a young age. This condition occurs when excess cholesterol in the bloodstream is deposited on the inner walls of blood vessels, particularly the arteries that supply blood to the heart (coronary arteries). The abnormal buildup of cholesterol forms clumps (plaques) that narrow and harden artery walls. As the plaques get bigger, they can clog the arteries and restrict the flow of blood to the heart. The buildup of plaques in coronary arteries causes a form of chest pain called angina and greatly increases a person's risk of having a heart attack.  https://medlineplus.gov/genetics/condition/familial-hypercholesterolemia

Clinical features

From HPO
Atherosclerosis
MedGen UID:
13948
Concept ID:
C0004153
Disease or Syndrome
A condition characterized by patchy atheromas or atherosclerotic plaques which develop in the walls of medium-sized and large arteries and can lead to arterial stenosis with reduced or blocked blood flow.
Tendon xanthomatosis
MedGen UID:
450999
Concept ID:
C0221253
Disease or Syndrome
The presence of xanthomas (intra-and extra-cellular accumulations of cholesterol) extensor tendons (typically over knuckles, Achilles tendon, knee, and elbows).
Hypercholesterolemia
MedGen UID:
5687
Concept ID:
C0020443
Disease or Syndrome
An increased concentration of cholesterol in the blood.
Hypertriglyceridemia
MedGen UID:
167238
Concept ID:
C0813230
Finding
An abnormal increase in the level of triglycerides in the blood.
Decreased LDL cholesterol concentration
MedGen UID:
776554
Concept ID:
C0853085
Finding
An decreased concentration of low-density lipoprotein cholesterol in the blood.

Professional guidelines

PubMed

Cegla J, Neely RDG, France M, Ferns G, Byrne CD, Halcox J, Datta D, Capps N, Shoulders C, Qureshi N, Rees A, Main L, Cramb R, Viljoen A, Payne J, Soran H; HEART UK Medical, Scientific and Research Committee
Atherosclerosis 2019 Dec;291:62-70. Epub 2019 Oct 14 doi: 10.1016/j.atherosclerosis.2019.10.011. PMID: 31704552

Curated

American College of Medical Genetics and Genomics, Genomic Testing (Secondary Findings) ACT Sheet, APOB, LDLR, PCSK9 Pathogenic Variants (Familial Hypercholesterolemia), 2019

The Cardiac Society of Australia and New Zealand, Diagnosis and Management of Familial Hypercholesterolaemia – Position Statement

Recent clinical studies

Etiology

Khalil YA, Rabès JP, Boileau C, Varret M
Atherosclerosis 2021 Jul;328:11-22. Epub 2021 May 23 doi: 10.1016/j.atherosclerosis.2021.05.007. PMID: 34058468
Wright RS, Ray KK, Raal FJ, Kallend DG, Jaros M, Koenig W, Leiter LA, Landmesser U, Schwartz GG, Friedman A, Wijngaard PLJ, Garcia Conde L, Kastelein JJP; ORION Phase III Investigators
J Am Coll Cardiol 2021 Mar 9;77(9):1182-1193. doi: 10.1016/j.jacc.2020.12.058. PMID: 33663735
Raal FJ, Rosenson RS, Reeskamp LF, Hovingh GK, Kastelein JJP, Rubba P, Ali S, Banerjee P, Chan KC, Gipe DA, Khilla N, Pordy R, Weinreich DM, Yancopoulos GD, Zhang Y, Gaudet D; ELIPSE HoFH Investigators
N Engl J Med 2020 Aug 20;383(8):711-720. doi: 10.1056/NEJMoa2004215. PMID: 32813947
Raal FJ, Kallend D, Ray KK, Turner T, Koenig W, Wright RS, Wijngaard PLJ, Curcio D, Jaros MJ, Leiter LA, Kastelein JJP; ORION-9 Investigators
N Engl J Med 2020 Apr 16;382(16):1520-1530. Epub 2020 Mar 18 doi: 10.1056/NEJMoa1913805. PMID: 32197277
Sniderman AD, Thanassoulis G, Glavinovic T, Navar AM, Pencina M, Catapano A, Ference BA
JAMA Cardiol 2019 Dec 1;4(12):1287-1295. doi: 10.1001/jamacardio.2019.3780. PMID: 31642874Free PMC Article

Diagnosis

Wright RS, Raal FJ, Koenig W, Landmesser U, Leiter LA, Vikarunnessa S, Lesogor A, Maheux P, Talloczy Z, Zang X, Schwartz GG, Ray KK
Cardiovasc Res 2024 Oct 14;120(12):1400-1410. doi: 10.1093/cvr/cvae109. PMID: 38753448Free PMC Article
Yanai H, Adachi H, Hakoshima M, Katsuyama H
Int J Mol Sci 2023 Sep 11;24(18) doi: 10.3390/ijms241813942. PMID: 37762244Free PMC Article
Khalil YA, Rabès JP, Boileau C, Varret M
Atherosclerosis 2021 Jul;328:11-22. Epub 2021 May 23 doi: 10.1016/j.atherosclerosis.2021.05.007. PMID: 34058468
Wright RS, Ray KK, Raal FJ, Kallend DG, Jaros M, Koenig W, Leiter LA, Landmesser U, Schwartz GG, Friedman A, Wijngaard PLJ, Garcia Conde L, Kastelein JJP; ORION Phase III Investigators
J Am Coll Cardiol 2021 Mar 9;77(9):1182-1193. doi: 10.1016/j.jacc.2020.12.058. PMID: 33663735
Falko JM
Endocr Pract 2018 Aug;24(8):756-763. doi: 10.4158/EP-2018-0157. PMID: 30183397

Therapy

Stroes ESG, Alexander VJ, Karwatowska-Prokopczuk E, Hegele RA, Arca M, Ballantyne CM, Soran H, Prohaska TA, Xia S, Ginsberg HN, Witztum JL, Tsimikas S; Balance Investigators
N Engl J Med 2024 May 16;390(19):1781-1792. Epub 2024 Apr 7 doi: 10.1056/NEJMoa2400201. PMID: 38587247
Wright RS, Ray KK, Raal FJ, Kallend DG, Jaros M, Koenig W, Leiter LA, Landmesser U, Schwartz GG, Friedman A, Wijngaard PLJ, Garcia Conde L, Kastelein JJP; ORION Phase III Investigators
J Am Coll Cardiol 2021 Mar 9;77(9):1182-1193. doi: 10.1016/j.jacc.2020.12.058. PMID: 33663735
Raal FJ, Rosenson RS, Reeskamp LF, Hovingh GK, Kastelein JJP, Rubba P, Ali S, Banerjee P, Chan KC, Gipe DA, Khilla N, Pordy R, Weinreich DM, Yancopoulos GD, Zhang Y, Gaudet D; ELIPSE HoFH Investigators
N Engl J Med 2020 Aug 20;383(8):711-720. doi: 10.1056/NEJMoa2004215. PMID: 32813947
Raal FJ, Kallend D, Ray KK, Turner T, Koenig W, Wright RS, Wijngaard PLJ, Curcio D, Jaros MJ, Leiter LA, Kastelein JJP; ORION-9 Investigators
N Engl J Med 2020 Apr 16;382(16):1520-1530. Epub 2020 Mar 18 doi: 10.1056/NEJMoa1913805. PMID: 32197277
Sniderman AD, Thanassoulis G, Glavinovic T, Navar AM, Pencina M, Catapano A, Ference BA
JAMA Cardiol 2019 Dec 1;4(12):1287-1295. doi: 10.1001/jamacardio.2019.3780. PMID: 31642874Free PMC Article

Prognosis

Bea AM, Larrea-Sebal A, Marco-Benedi V, Uribe KB, Galicia-Garcia U, Lamiquiz-Moneo I, Laclaustra M, Moreno-Franco B, Fernandez-Corredoira P, Olmos S, Civeira F, Martin C, Cenarro A
Arterioscler Thromb Vasc Biol 2023 Jun;43(6):1066-1077. Epub 2023 Apr 13 doi: 10.1161/ATVBAHA.123.318977. PMID: 37051929
Khalil YA, Rabès JP, Boileau C, Varret M
Atherosclerosis 2021 Jul;328:11-22. Epub 2021 May 23 doi: 10.1016/j.atherosclerosis.2021.05.007. PMID: 34058468
Gouni-Berthold I, Alexander VJ, Yang Q, Hurh E, Steinhagen-Thiessen E, Moriarty PM, Hughes SG, Gaudet D, Hegele RA, O'Dea LSL, Stroes ESG, Tsimikas S, Witztum JL; COMPASS study group
Lancet Diabetes Endocrinol 2021 May;9(5):264-275. Epub 2021 Mar 30 doi: 10.1016/S2213-8587(21)00046-2. PMID: 33798466
D'Erasmo L, Di Costanzo A, Arca M
Curr Opin Lipidol 2020 Apr;31(2):56-61. doi: 10.1097/MOL.0000000000000664. PMID: 32011344
Baass A, Paquette M, Bernard S, Hegele RA
J Intern Med 2020 Apr;287(4):340-348. Epub 2020 Jan 8 doi: 10.1111/joim.13016. PMID: 31840878

Clinical prediction guides

Wright RS, Raal FJ, Koenig W, Landmesser U, Leiter LA, Vikarunnessa S, Lesogor A, Maheux P, Talloczy Z, Zang X, Schwartz GG, Ray KK
Cardiovasc Res 2024 Oct 14;120(12):1400-1410. doi: 10.1093/cvr/cvae109. PMID: 38753448Free PMC Article
Santos RD, Wiegman A, Caprio S, Cariou B, Averna M, Poulouin Y, Scemama M, Manvelian G, Garon G, Daniels S
JAMA Pediatr 2024 Mar 1;178(3):283-293. doi: 10.1001/jamapediatrics.2023.6477. PMID: 38315470Free PMC Article
Yanai H, Adachi H, Hakoshima M, Katsuyama H
Int J Mol Sci 2023 Sep 11;24(18) doi: 10.3390/ijms241813942. PMID: 37762244Free PMC Article
Sniderman AD, Thanassoulis G, Glavinovic T, Navar AM, Pencina M, Catapano A, Ference BA
JAMA Cardiol 2019 Dec 1;4(12):1287-1295. doi: 10.1001/jamacardio.2019.3780. PMID: 31642874Free PMC Article
Gencer B, Lambert G, Mach F
Swiss Med Wkly 2015;145:w14094. Epub 2015 Apr 9 doi: 10.4414/smw.2015.14094. PMID: 25856746

Recent systematic reviews

Peng W, Qiang F, Peng W, Qian Z, Ke Z, Yi L, Jian Z, Chongrong Q
Int J Cardiol 2016 Nov 1;222:119-129. Epub 2016 Jul 30 doi: 10.1016/j.ijcard.2016.07.239. PMID: 27494723
Gouni-Berthold I, Descamps OS, Fraass U, Hartfield E, Allcott K, Dent R, März W
Br J Clin Pharmacol 2016 Dec;82(6):1412-1443. Epub 2016 Oct 4 doi: 10.1111/bcp.13066. PMID: 27478094Free PMC Article
Turgeon RD, Barry AR, Pearson GJ
Can Fam Physician 2016 Jan;62(1):32-7. PMID: 26796832Free PMC Article

Supplemental Content

Table of contents

    Clinical resources

    Practice guidelines

    • PubMed
      See practice and clinical guidelines in PubMed. The search results may include broader topics and may not capture all published guidelines. See the FAQ for details.

    Curated

    • ACMG ACT, 2019
      American College of Medical Genetics and Genomics, Genomic Testing (Secondary Findings) ACT Sheet, APOB, LDLR, PCSK9 Pathogenic Variants (Familial Hypercholesterolemia), 2019
    • CSANZ, 2016
      The Cardiac Society of Australia and New Zealand, Diagnosis and Management of Familial Hypercholesterolaemia – Position Statement

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