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Hemochromatosis type 4(HFE4)

MedGen UID:
340044
Concept ID:
C1853733
Disease or Syndrome
Synonyms: Hemochromatosis due to defect in ferroportin; Hemochromatosis, autosomal dominant; HFE4; SLC40A1-Related Hereditary Hemochromatosis
SNOMED CT: Hemochromatosis type 4 (719975002); Autosomal dominant hereditary hemochromatosis (719975002); Ferroportin disease (719975002); Hemochromatosis due to defect in ferroportin (719975002)
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
 
Gene (location): SLC40A1 (2q32.2)
 
Monarch Initiative: MONDO:0011631
OMIM®: 606069
Orphanet: ORPHA139491

Definition

Hemochromatosis type 4 (HFE4) is a dominantly inherited iron overload disorder with heterogeneous phenotypic manifestations that can be classified into 2 groups. One group is characterized by an early rise in ferritin (see 134790) levels with low to normal transferrin (190000) saturation and iron accumulation predominantly in macrophages. The other group is similar to classical hemochromatosis, with high transferrin saturation and prominent parenchymal iron loading (summary by De Domenico et al., 2005). For general background information and a discussion of genetic heterogeneity of hereditary hemochromatosis, see 235200. [from OMIM]

Clinical features

From HPO
Arthralgia
MedGen UID:
13917
Concept ID:
C0003862
Sign or Symptom
Joint pain.
Fatigue
MedGen UID:
41971
Concept ID:
C0015672
Sign or Symptom
A subjective feeling of tiredness characterized by a lack of energy and motivation.
Impotence
MedGen UID:
1720680
Concept ID:
CN208474
Finding
Inability to develop or maintain an erection of the penis.
Cardiac arrhythmia
MedGen UID:
2039
Concept ID:
C0003811
Finding
Any cardiac rhythm other than the normal sinus rhythm. Such a rhythm may be either of sinus or ectopic origin and either regular or irregular. An arrhythmia may be due to a disturbance in impulse formation or conduction or both.
Cardiomyopathy
MedGen UID:
209232
Concept ID:
C0878544
Disease or Syndrome
A myocardial disorder in which the heart muscle is structurally and functionally abnormal, in the absence of coronary artery disease, hypertension, valvular disease and congenital heart disease sufficient to cause the observed myocardial abnormality.
Hepatomegaly
MedGen UID:
42428
Concept ID:
C0019209
Finding
Abnormally increased size of the liver.
Cirrhosis of liver
MedGen UID:
7368
Concept ID:
C0023890
Disease or Syndrome
A chronic disorder of the liver in which liver tissue becomes scarred and is partially replaced by regenerative nodules and fibrotic tissue resulting in loss of liver function.
Hepatic steatosis
MedGen UID:
398225
Concept ID:
C2711227
Disease or Syndrome
Steatosis is a term used to denote lipid accumulation within hepatocytes.
Anemia
MedGen UID:
1526
Concept ID:
C0002871
Disease or Syndrome
A reduction in erythrocytes volume or hemoglobin concentration.
Osteoarthritis
MedGen UID:
45244
Concept ID:
C0029408
Disease or Syndrome
Osteoarthritis (OA) is a degenerative disease of the joints characterized by degradation of the hyaline articular cartilage and remodeling of the subchondral bone with sclerosis (Meulenbelt et al., 2006). Clinical problems include pain and joint stiffness often leading to significant disability and joint replacement. Osteoarthritis exhibits a clear predilection for specific joints; it appears most commonly in the hip and knee joints and lumbar and cervical spine, as well as in the distal interphalangeal and the first carpometacarpal (base of thumb) and proximal interphalangeal joints of the hand; however, patients with osteoarthritis may have 1, a few, or all of these sites affected (Stefansson et al., 2003). According to a conservative estimate, greater than 70% of the population of the United States at age 65 years is affected by the disease, reflecting its age dependence. Genetic Heterogeneity of Susceptibility to Osteoarthritis Susceptibility to osteoarthritis has been associated with variation in other genes: OS2 (140600) with variation in the MATN3 gene (602109) on chromosome 2p24; OS3 (607850) with variation in the ASPN gene (608135) on chromosome 9q22; and OS5 (612400) with variation in the GDF5 gene (601146) on chromosome 20q11. Other susceptibility loci for osteoarthritis have been mapped to chromosomes 2q33 (OS4; 610839) and 3p24 (OS6; 612401).
Diabetes mellitus
MedGen UID:
8350
Concept ID:
C0011849
Disease or Syndrome
A group of abnormalities characterized by hyperglycemia and glucose intolerance.
Impaired glucose tolerance
MedGen UID:
852424
Concept ID:
C0151671
Finding
An abnormal resistance to glucose, i.e., a reduction in the ability to maintain glucose levels in the blood stream within normal limits following oral or intravenous administration of glucose.
Increased circulating ferritin concentration
MedGen UID:
69130
Concept ID:
C0241013
Finding
Increased concentration of ferritin in the blood circulation.
Glucose intolerance
MedGen UID:
75760
Concept ID:
C0271650
Disease or Syndrome
Glucose intolerance (GI) can be defined as dysglycemia that comprises both prediabetes and diabetes. It includes the conditions of impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) and diabetes mellitus (DM).
Elevated transferrin saturation
MedGen UID:
868498
Concept ID:
C4022892
Finding
An above normal level of saturation of serum transferrin with iron.
Hyperpigmentation of the skin
MedGen UID:
57992
Concept ID:
C0162834
Pathologic Function
A darkening of the skin related to an increase in melanin production and deposition.
Cataract
MedGen UID:
39462
Concept ID:
C0086543
Disease or Syndrome
A cataract is an opacity or clouding that develops in the crystalline lens of the eye or in its capsule.

Professional guidelines

PubMed

Majore S, Bonaccorsi di Patti MC, Valiante M, Polticelli F, Cortese A, Di Bartolomeo S, De Bernardo C, De Muro M, Faienza F, Radio FC, Grammatico P, Musci G
Biochim Biophys Acta Mol Basis Dis 2018 Feb;1864(2):464-470. Epub 2017 Nov 14 doi: 10.1016/j.bbadis.2017.11.006. PMID: 29154924

Recent clinical studies

Etiology

Hayashi H, Yano M, Urawa N, Mizutani A, Hamaoka S, Araki J, Kojima Y, Naito Y, Kato A, Tatsumi Y, Kato K
Intern Med 2018 Oct 1;57(19):2865-2871. Epub 2018 May 18 doi: 10.2169/internalmedicine.0481-17. PMID: 29780118Free PMC Article
Majore S, Bonaccorsi di Patti MC, Valiante M, Polticelli F, Cortese A, Di Bartolomeo S, De Bernardo C, De Muro M, Faienza F, Radio FC, Grammatico P, Musci G
Biochim Biophys Acta Mol Basis Dis 2018 Feb;1864(2):464-470. Epub 2017 Nov 14 doi: 10.1016/j.bbadis.2017.11.006. PMID: 29154924
Kasvosve I
Clin Chim Acta 2013 Feb 1;416:20-5. Epub 2012 Nov 21 doi: 10.1016/j.cca.2012.11.013. PMID: 23178444

Diagnosis

Hu J, Li Y, Zhang L, Peng G, Zhang F, Zhao X
Med Mol Morphol 2023 Sep;56(3):233-238. Epub 2023 Jun 29 doi: 10.1007/s00795-023-00359-8. PMID: 37382698
Wu LY, Song ZY, Li QH, Mou LJ, Yu YY, Shen SS, Song XX
Medicine (Baltimore) 2021 Apr 2;100(13):e25258. doi: 10.1097/MD.0000000000025258. PMID: 33787609Free PMC Article
Majore S, Bonaccorsi di Patti MC, Valiante M, Polticelli F, Cortese A, Di Bartolomeo S, De Bernardo C, De Muro M, Faienza F, Radio FC, Grammatico P, Musci G
Biochim Biophys Acta Mol Basis Dis 2018 Feb;1864(2):464-470. Epub 2017 Nov 14 doi: 10.1016/j.bbadis.2017.11.006. PMID: 29154924
Zhang W, Lv T, Huang J, Ou X
Medicine (Baltimore) 2017 Sep;96(38):e8064. doi: 10.1097/MD.0000000000008064. PMID: 28930842Free PMC Article
Brissot P, Troadec MB, Bardou-Jacquet E, Le Lan C, Jouanolle AM, Deugnier Y, Loréal O
Blood Rev 2008 Jul;22(4):195-210. Epub 2008 Apr 21 doi: 10.1016/j.blre.2008.03.001. PMID: 18430498

Therapy

Wu LY, Song ZY, Li QH, Mou LJ, Yu YY, Shen SS, Song XX
Medicine (Baltimore) 2021 Apr 2;100(13):e25258. doi: 10.1097/MD.0000000000025258. PMID: 33787609Free PMC Article
Seo YA, Elkhader JA, Wessling-Resnick M
Biometals 2016 Feb;29(1):147-55. Epub 2015 Dec 22 doi: 10.1007/s10534-015-9904-2. PMID: 26693922Free PMC Article
Brissot P, Troadec MB, Bardou-Jacquet E, Le Lan C, Jouanolle AM, Deugnier Y, Loréal O
Blood Rev 2008 Jul;22(4):195-210. Epub 2008 Apr 21 doi: 10.1016/j.blre.2008.03.001. PMID: 18430498

Prognosis

Le Tertre M, Ka C, Raud L, Berlivet I, Gourlaouen I, Richard G, Uguen K, Chen JM, Férec C, Fichou Y, Le Gac G
Blood Cells Mol Dis 2021 Mar;87:102527. Epub 2020 Dec 8 doi: 10.1016/j.bcmd.2020.102527. PMID: 33341511
Hayashi H, Yano M, Urawa N, Mizutani A, Hamaoka S, Araki J, Kojima Y, Naito Y, Kato A, Tatsumi Y, Kato K
Intern Med 2018 Oct 1;57(19):2865-2871. Epub 2018 May 18 doi: 10.2169/internalmedicine.0481-17. PMID: 29780118Free PMC Article
Majore S, Bonaccorsi di Patti MC, Valiante M, Polticelli F, Cortese A, Di Bartolomeo S, De Bernardo C, De Muro M, Faienza F, Radio FC, Grammatico P, Musci G
Biochim Biophys Acta Mol Basis Dis 2018 Feb;1864(2):464-470. Epub 2017 Nov 14 doi: 10.1016/j.bbadis.2017.11.006. PMID: 29154924
Le Gac G, Ka C, Joubrel R, Gourlaouen I, Lehn P, Mornon JP, Férec C, Callebaut I
Hum Mutat 2013 Oct;34(10):1371-80. Epub 2013 Sep 10 doi: 10.1002/humu.22369. PMID: 23784628
Ponka P
Semin Hematol 2002 Oct;39(4):249-62. doi: 10.1053/shem.2002.35638. PMID: 12382200

Clinical prediction guides

Le Tertre M, Ka C, Raud L, Berlivet I, Gourlaouen I, Richard G, Uguen K, Chen JM, Férec C, Fichou Y, Le Gac G
Blood Cells Mol Dis 2021 Mar;87:102527. Epub 2020 Dec 8 doi: 10.1016/j.bcmd.2020.102527. PMID: 33341511
Ka C, Guellec J, Pepermans X, Kannengiesser C, Ged C, Wuyts W, Cassiman D, de Ledinghen V, Varet B, de Kerguenec C, Oudin C, Gourlaouen I, Lefebvre T, Férec C, Callebaut I, Le Gac G
Haematologica 2018 Nov;103(11):1796-1805. Epub 2018 Jul 12 doi: 10.3324/haematol.2018.189845. PMID: 30002125Free PMC Article
Majore S, Bonaccorsi di Patti MC, Valiante M, Polticelli F, Cortese A, Di Bartolomeo S, De Bernardo C, De Muro M, Faienza F, Radio FC, Grammatico P, Musci G
Biochim Biophys Acta Mol Basis Dis 2018 Feb;1864(2):464-470. Epub 2017 Nov 14 doi: 10.1016/j.bbadis.2017.11.006. PMID: 29154924
Seo YA, Elkhader JA, Wessling-Resnick M
Biometals 2016 Feb;29(1):147-55. Epub 2015 Dec 22 doi: 10.1007/s10534-015-9904-2. PMID: 26693922Free PMC Article
Ponka P
Semin Hematol 2002 Oct;39(4):249-62. doi: 10.1053/shem.2002.35638. PMID: 12382200

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