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Hypercholesterolemia, familial, 1(FH; FHCL1)

MedGen UID:
152875
Concept ID:
C0745103
Disease or Syndrome
Synonyms: 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
SNOMED CT: Fredrickson type IIa hyperlipoproteinemia (397915002)
 
Genes (locations): APOA2 (1q23.3); EPHX2 (8p21.2-21.1); GHR (5p13.1-12); LDLR (19p13.2); PPP1R17 (7p14.3)
 
Monarch Initiative: MONDO:0007750
OMIM®: 143890

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 description

From OMIM
Familial hypercholesterolemia is 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 (Hobbs et al., 1992). The FHCL1 phenotype can be modified by mutation in other genes. For example, in individuals with the LDLR mutation IVS14+1G-A (606945.0063), the phenotype can be altered by a SNP in the APOA2 gene (107670.0002), a SNP in the EPHX2 gene (132811.0001), or a SNP in the GHR gene (600946.0028). Genetic Heterogeneity of Familial Hypercholesterolemia Other forms of monogenic familial hypercholesterolemia include FHCL2 (144010), caused by mutation in the APOB gene (107730); FHCL3 (603776), caused by mutation in the PCSK9 gene (607786); and FHCL4 (603813), caused by mutation in the LDLRAP1 gene (605747).  http://www.omim.org/entry/143890

Clinical features

From HPO
Coronary artery atherosclerosis
MedGen UID:
3623
Concept ID:
C0010054
Disease or Syndrome
Reduction of the diameter of the coronary arteries as the result of an accumulation of atheromatous plaques within the walls of the coronary arteries, which increases the risk of myocardial ischemia.
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).
Elevated circulating LDL-C concentration
MedGen UID:
154289
Concept ID:
C0549399
Finding
The concentration of low-density lipoprotein cholesterol in the blood circulation is above the upper limit of normal.
Xanthelasma
MedGen UID:
56357
Concept ID:
C0155210
Disease or Syndrome
The presence of xanthomata in the skin of the eyelid.
Arcus senilis
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.

Recent clinical studies

Etiology

Abifadel M, Boileau C
J Intern Med 2023 Feb;293(2):144-165. Epub 2022 Oct 17 doi: 10.1111/joim.13577. PMID: 36196022Free PMC Article
McGowan MP, Hosseini Dehkordi SH, Moriarty PM, Duell PB
J Am Heart Assoc 2019 Dec 17;8(24):e013225. Epub 2019 Dec 16 doi: 10.1161/JAHA.119.013225. PMID: 31838973Free PMC Article
Teramoto T, Sasaki J, Ishibashi S, Birou S, Daida H, Dohi S, Egusa G, Hiro T, Hirobe K, Iida M, Kihara S, Kinoshita M, Maruyama C, Ohta T, Okamura T, Yamashita S, Yokode M, Yokote K, Harada-Shiba M, Arai H, Bujo H, Nohara A, Ohta T, Oikawa S, Okada T, Wakatsuki A
J Atheroscler Thromb 2014;21(1):6-10. Epub 2013 Dec 10 doi: 10.5551/jat.20040. PMID: 24335046
Thompson GR
Curr Opin Lipidol 2010 Dec;21(6):487-91. doi: 10.1097/MOL.0b013e32833e13fd. PMID: 21206339
Am J Cardiovasc Drugs 2010;10(4):271-9. doi: 10.2165/11533460-000000000-00000. PMID: 20653334

Diagnosis

Reamy BV
Am Fam Physician 2024 Sep;110(3):226. PMID: 39283842
Abifadel M, Boileau C
J Intern Med 2023 Feb;293(2):144-165. Epub 2022 Oct 17 doi: 10.1111/joim.13577. PMID: 36196022Free PMC Article
Loh WJ, Watts GF
Endocrinol Metab Clin North Am 2022 Sep;51(3):511-537. Epub 2022 Jul 4 doi: 10.1016/j.ecl.2022.02.006. PMID: 35963626
McGowan MP, Hosseini Dehkordi SH, Moriarty PM, Duell PB
J Am Heart Assoc 2019 Dec 17;8(24):e013225. Epub 2019 Dec 16 doi: 10.1161/JAHA.119.013225. PMID: 31838973Free PMC Article
Teramoto T, Sasaki J, Ishibashi S, Birou S, Daida H, Dohi S, Egusa G, Hiro T, Hirobe K, Iida M, Kihara S, Kinoshita M, Maruyama C, Ohta T, Okamura T, Yamashita S, Yokode M, Yokote K, Harada-Shiba M, Arai H, Bujo H, Nohara A, Ohta T, Oikawa S, Okada T, Wakatsuki A
J Atheroscler Thromb 2014;21(1):6-10. Epub 2013 Dec 10 doi: 10.5551/jat.20040. PMID: 24335046

Therapy

Ballantyne CM, Gellis L, Tardif JC, Banka P, Navar AM, Asprusten EA, Scott R, Stroes ESG, Froman S, Mendizabal G, Wang F, Catapano AL
JAMA 2026 Jan 13;335(2):129-139. doi: 10.1001/jama.2025.20620. PMID: 41206969Free PMC Article
Reamy BV
Am Fam Physician 2024 Sep;110(3):226. PMID: 39283842
Raal F, Fourie N, Scott R, Blom D, De Vries Basson M, Kayikcioglu M, Caldwell K, Kallend D, Stein E; LIBerate-HeFH Investigators
Eur Heart J 2023 Oct 21;44(40):4272-4280. doi: 10.1093/eurheartj/ehad596. PMID: 37639462Free PMC Article
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
Am J Cardiovasc Drugs 2010;10(4):271-9. doi: 10.2165/11533460-000000000-00000. PMID: 20653334

Prognosis

Thompson GR
J Lipid Res 2021;62:100036. Epub 2021 Feb 6 doi: 10.1194/jlr.TR120001001. PMID: 32651185Free PMC Article
Lazarte J, Hegele RA
Can J Cardiol 2020 Sep;36(9):1362-1371. Epub 2020 Mar 23 doi: 10.1016/j.cjca.2020.03.020. PMID: 32640212
Luirink IK, Wiegman A, Kusters DM, Hof MH, Groothoff JW, de Groot E, Kastelein JJP, Hutten BA
N Engl J Med 2019 Oct 17;381(16):1547-1556. doi: 10.1056/NEJMoa1816454. PMID: 31618540
Kolovou GD, Kostakou PM, Anagnostopoulou KK
Int J Cardiol 2011 Mar 17;147(3):349-58. Epub 2010 Sep 9 doi: 10.1016/j.ijcard.2010.08.009. PMID: 20826022
Seth RK, Gulati S, Seth S, Menon PS, Kalra V
Indian J Pediatr 2004 Jan;71(1):97-9. doi: 10.1007/BF02725665. PMID: 14979394

Clinical prediction guides

Le A, Peng H, Golinsky D, Di Scipio M, Lali R, Paré G
Curr Atheroscler Rep 2024 Jun;26(6):189-203. Epub 2024 Apr 4 doi: 10.1007/s11883-024-01200-y. PMID: 38573470
Paquette M, Baass A
Adv Clin Chem 2024;119:167-201. Epub 2024 Mar 6 doi: 10.1016/bs.acc.2024.02.004. PMID: 38514210
Tokgozoglu L, Kayikcioglu M
Curr Cardiol Rep 2021 Sep 4;23(10):151. doi: 10.1007/s11886-021-01565-5. PMID: 34480646
Lazarte J, Hegele RA
Can J Cardiol 2020 Sep;36(9):1362-1371. Epub 2020 Mar 23 doi: 10.1016/j.cjca.2020.03.020. PMID: 32640212
Kolovou GD, Kostakou PM, Anagnostopoulou KK
Int J Cardiol 2011 Mar 17;147(3):349-58. Epub 2010 Sep 9 doi: 10.1016/j.ijcard.2010.08.009. PMID: 20826022

Recent systematic reviews

Ho VQT, Tran NB, Nguyen N, Arrighini GS, Downes D, Dandamudi M, Ferrara VZ, Ho THQ, Walia H, Barbagelata A, Leucker TM, Giorgi J
Open Heart 2025 Aug 21;12(2) doi: 10.1136/openhrt-2025-003490. PMID: 40841123Free PMC Article
Vaseghi G, Javanmard SH, Heshmat-Ghahdarijani K, Sarrafzadegan N, Amerizadeh A
Curr Probl Cardiol 2023 May;48(5):101109. Epub 2022 Jan 7 doi: 10.1016/j.cpcardiol.2022.101109. PMID: 35007640
Hu P, Dharmayat KI, Stevens CAT, Sharabiani MTA, Jones RS, Watts GF, Genest J, Ray KK, Vallejo-Vaz AJ
Circulation 2020 Jun 2;141(22):1742-1759. Epub 2020 May 29 doi: 10.1161/CIRCULATIONAHA.119.044795. PMID: 32468833
Beheshti SO, Madsen CM, Varbo A, Nordestgaard BG
J Am Coll Cardiol 2020 May 26;75(20):2553-2566. doi: 10.1016/j.jacc.2020.03.057. PMID: 32439005
Rosenson RS, Hegele RA, Koenig W
Circ Res 2019 Feb;124(3):364-385. doi: 10.1161/CIRCRESAHA.118.313238. PMID: 30702994

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.
    • Bookshelf
      See practice and clinical guidelines in NCBI Bookshelf. 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
    • NICE, 2019
      National Institute for Health and Clinical Excellence, Identification and management of familial hypercholesterolaemia, 2008 [Updated: 4 October 2019]

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