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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]
Full text of GeneReview (by section):
Summary  |  Diagnosis  |  Clinical Characteristics  |  Genetically Related (Allelic) Disorders  |  Differential Diagnosis  |  Management  |  Genetic Counseling  |  Resources  |  Molecular Genetics  |  Chapter Notes  |  References
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.
See: Feature record | Search on this feature
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).
See: Feature record | Search on this feature
Increased LDL cholesterol concentration
MedGen UID:
154289
•Concept ID:
C0549399
•
Finding
An elevated concentration of low-density lipoprotein cholesterol in the blood.
See: Feature record | Search on this feature
Xanthelasma
MedGen UID:
56357
•Concept ID:
C0155210
•
Disease or Syndrome
The presence of xanthomata in the skin of the eyelid.
See: Feature record | Search on this feature
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.
See: Feature record | Search on this feature
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Recent clinical studies

Etiology

International Atherosclerosis Society guidance for implementing best practice in the care of familial hypercholesterolaemia.
Watts GF, Gidding SS, Hegele RA, Raal FJ, Sturm AC, Jones LK, Sarkies MN, Al-Rasadi K, Blom DJ, Daccord M, de Ferranti SD, Folco E, Libby P, Mata P, Nawawi HM, Ramaswami U, Ray KK, Stefanutti C, Yamashita S, Pang J, Thompson GR, Santos RD
Nat Rev Cardiol 2023 Dec;20(12):845-869. Epub 2023 Jun 15 doi: 10.1038/s41569-023-00892-0. PMID: 37322181
Genetic and molecular architecture of familial hypercholesterolemia.
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
Familial Hypercholesterolemia and Its Current Diagnostics and Treatment Possibilities: A Literature Analysis.
Zubielienė K, Valterytė G, Jonaitienė N, Žaliaduonytė D, Zabiela V
Medicina (Kaunas) 2022 Nov 17;58(11) doi: 10.3390/medicina58111665. PMID: 36422206Free PMC Article
Familial Hypercholesterolemia: Global Burden and Approaches.
Tokgozoglu L, Kayikcioglu M
Curr Cardiol Rep 2021 Sep 4;23(10):151. doi: 10.1007/s11886-021-01565-5. PMID: 34480646
Diagnosis and Treatment of Heterozygous Familial Hypercholesterolemia.
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

Diagnosis

Genetic and molecular architecture of familial hypercholesterolemia.
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
Familial Hypercholesterolemia and Its Current Diagnostics and Treatment Possibilities: A Literature Analysis.
Zubielienė K, Valterytė G, Jonaitienė N, Žaliaduonytė D, Zabiela V
Medicina (Kaunas) 2022 Nov 17;58(11) doi: 10.3390/medicina58111665. PMID: 36422206Free PMC Article
Familial Hypercholesterolemia: Global Burden and Approaches.
Tokgozoglu L, Kayikcioglu M
Curr Cardiol Rep 2021 Sep 4;23(10):151. doi: 10.1007/s11886-021-01565-5. PMID: 34480646
Diagnosis and Treatment of Heterozygous Familial Hypercholesterolemia.
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
Familial hypercholesterolemia--epidemiology, diagnosis, and screening.
Singh S, Bittner V
Curr Atheroscler Rep 2015;17(2):482. doi: 10.1007/s11883-014-0482-5. PMID: 25612857

Therapy

Familial Hypercholesterolemia: Global Burden and Approaches.
Tokgozoglu L, Kayikcioglu M
Curr Cardiol Rep 2021 Sep 4;23(10):151. doi: 10.1007/s11886-021-01565-5. PMID: 34480646
Pooled Patient-Level Analysis of Inclisiran Trials in Patients With Familial Hypercholesterolemia or Atherosclerosis.
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
Familial hypercholesterolaemia.
Defesche JC, Gidding SS, Harada-Shiba M, Hegele RA, Santos RD, Wierzbicki AS
Nat Rev Dis Primers 2017 Dec 7;3:17093. doi: 10.1038/nrdp.2017.93. PMID: 29219151
Familial hypercholesterolemia.
Bouhairie VE, Goldberg AC
Cardiol Clin 2015 May;33(2):169-79. doi: 10.1016/j.ccl.2015.01.001. PMID: 25939291Free PMC Article
Familial hypercholesterolemia--epidemiology, diagnosis, and screening.
Singh S, Bittner V
Curr Atheroscler Rep 2015;17(2):482. doi: 10.1007/s11883-014-0482-5. PMID: 25612857

Prognosis

Familial Hypercholesterolemia: Global Burden and Approaches.
Tokgozoglu L, Kayikcioglu M
Curr Cardiol Rep 2021 Sep 4;23(10):151. doi: 10.1007/s11886-021-01565-5. PMID: 34480646
Prevalence and Treatment of Familial Hypercholesterolemia in France.
Bérard E, Bongard V, Haas B, Dallongeville J, Moitry M, Cottel D, Ruidavets JB, Ferrières J
Can J Cardiol 2019 Jun;35(6):744-752. Epub 2019 Feb 27 doi: 10.1016/j.cjca.2019.02.013. PMID: 31151710
The complex molecular genetics of familial hypercholesterolaemia.
Berberich AJ, Hegele RA
Nat Rev Cardiol 2019 Jan;16(1):9-20. doi: 10.1038/s41569-018-0052-6. PMID: 29973710
Epidemiology of familial hypercholesterolaemia: Community and clinical.
Vallejo-Vaz AJ, Ray KK
Atherosclerosis 2018 Oct;277:289-297. doi: 10.1016/j.atherosclerosis.2018.06.855. PMID: 30270061
Unusual genetic variants associated with hypercholesterolemia in Argentina.
Corral P, Geller AS, Polisecki EY, Lopez GI, Bañares VG, Cacciagiu L, Berg G, Hegele RA, Schaefer EJ, Schreier LE
Atherosclerosis 2018 Oct;277:256-261. doi: 10.1016/j.atherosclerosis.2018.06.009. PMID: 30270055

Clinical prediction guides

Familial Hypercholesterolemia: Global Burden and Approaches.
Tokgozoglu L, Kayikcioglu M
Curr Cardiol Rep 2021 Sep 4;23(10):151. doi: 10.1007/s11886-021-01565-5. PMID: 34480646
Genetic spectrum of familial hypercholesterolemia and correlations with clinical expression: Implications for diagnosis improvement.
Di Taranto MD, Giacobbe C, Palma D, Iannuzzo G, Gentile M, Calcaterra I, Guardamagna O, Auricchio R, Di Minno MND, Fortunato G
Clin Genet 2021 Nov;100(5):529-541. Epub 2021 Aug 3 doi: 10.1111/cge.14036. PMID: 34297352Free PMC Article
Prevalence and Treatment of Familial Hypercholesterolemia in France.
Bérard E, Bongard V, Haas B, Dallongeville J, Moitry M, Cottel D, Ruidavets JB, Ferrières J
Can J Cardiol 2019 Jun;35(6):744-752. Epub 2019 Feb 27 doi: 10.1016/j.cjca.2019.02.013. PMID: 31151710
Molecular diagnosis of familial hypercholesterolaemia.
Graham CA, Latten MJ, Hart PJ
Curr Opin Lipidol 2017 Aug;28(4):313-320. doi: 10.1097/MOL.0000000000000430. PMID: 28463860
Polygenic Versus Monogenic Causes of Hypercholesterolemia Ascertained Clinically.
Wang J, Dron JS, Ban MR, Robinson JF, McIntyre AD, Alazzam M, Zhao PJ, Dilliott AA, Cao H, Huff MW, Rhainds D, Low-Kam C, Dubé MP, Lettre G, Tardif JC, Hegele RA
Arterioscler Thromb Vasc Biol 2016 Dec;36(12):2439-2445. Epub 2016 Oct 20 doi: 10.1161/ATVBAHA.116.308027. PMID: 27765764

Recent systematic reviews

Familial Hypercholesterolemia (FH) Registry Worldwide: A Systematic Review.
Amerizadeh A, Javanmard SH, Sarrafzadegan N, Vaseghi G
Curr Probl Cardiol 2022 Oct;47(10):100999. Epub 2021 Sep 24 doi: 10.1016/j.cpcardiol.2021.100999. PMID: 34571102
Diet and Cardiovascular Disease Risk Among Individuals with Familial Hypercholesterolemia: Systematic Review and Meta-Analysis.
Barkas F, Nomikos T, Liberopoulos E, Panagiotakos D
Nutrients 2020 Aug 13;12(8) doi: 10.3390/nu12082436. PMID: 32823643Free PMC Article
Prevalence of Familial Hypercholesterolemia Among the General Population and Patients With Atherosclerotic Cardiovascular Disease: A Systematic Review and Meta-Analysis.
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
Worldwide Prevalence of Familial Hypercholesterolemia: Meta-Analyses of 11 Million Subjects.
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
Cholesterol-Lowering Agents.
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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