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Hemochromatosis type 3(HFE3)

MedGen UID:
388114
Concept ID:
C1858664
Disease or Syndrome
Synonyms: Hemochromatosis due to defect in transferrin receptor 2; HFE3; TFR2-Related Hereditary Hemochromatosis
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Sources: HPO, OMIM, 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 homozygotes. In the context of medical genetics, autosomal recessive disorders manifest in homozygotes (with two copies of the mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
Autosomal recessive inheritance (HPO, OMIM, Orphanet)
SNOMED CT: Hemochromatosis type 3 (719974003); TFR2 (transferrin receptor 2 gene) related hemochromatosis (719974003)
 
Gene (location): TFR2 (7q22.1)
OMIM®: 604250
Orphanet: ORPHA225123

Disease characteristics

Excerpted from the GeneReview: TFR2-Related Hereditary Hemochromatosis
TFR2-related hereditary hemochromatosis (TFR2-HHC) is characterized by increased intestinal iron absorption resulting in iron accumulation in the liver, heart, pancreas, and endocrine organs. Age of onset is earlier than in HFE-associated HHC. Some individuals present in the second decade and others present as adults with fatigue and arthralgia and/or organ involvement including liver cirrhosis, diabetes mellitus, and arthropathy. In other individuals, TFR2-HHC may not be progressive even if untreated. [from GeneReviews]
Authors:
Clara Camaschella  |  Antonella Roetto   view full author information

Additional description

From GHR
Hereditary hemochromatosis is a disorder that causes the body to absorb too much iron from the diet. The excess iron is stored in the body's tissues and organs, particularly the skin, heart, liver, pancreas, and joints. Because humans cannot increase the excretion of iron, excess iron can overload and eventually damage tissues and organs. For this reason, hereditary hemochromatosis is also called an iron overload disorder.Early symptoms of hereditary hemochromatosis are nonspecific and may include fatigue, joint pain, abdominal pain, and loss of sex drive. Later signs and symptoms can include arthritis, liver disease, diabetes, heart abnormalities, and skin discoloration. The appearance and progression of symptoms can be affected by environmental and lifestyle factors such as the amount of iron in the diet, alcohol use, and infections.Hereditary hemochromatosis is classified by type depending on the age of onset and other factors such as genetic cause and mode of inheritance. Type 1, the most common form of the disorder, and type 4 (also called ferroportin disease) begin in adulthood. Men with type 1 or type 4 hemochromatosis typically develop symptoms between the ages of 40 and 60, and women usually develop symptoms after menopause.Type 2 hemochromatosis is a juvenile-onset disorder. Iron accumulation begins early in life, and symptoms may appear in childhood. By age 20, decreased or absent secretion of sex hormones is evident. Females usually begin menstruation in a normal manner, but menses stop after a few years. Males may experience delayed puberty or symptoms related to a shortage of sex hormones. If the disorder is untreated, heart disease becomes evident by age 30.The onset of type 3 hemochromatosis is usually intermediate between types 1 and 2. Symptoms of type 3 hemochromatosis generally begin before age 30.  https://ghr.nlm.nih.gov/condition/hereditary-hemochromatosis

Clinical features

Hypogonadotropic hypogonadism 7 with or without anosmia
MedGen UID:
82883
Concept ID:
C0271623
Disease or Syndrome
Isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD) is characterized by inappropriately low serum concentrations of the gonadotropins LH (luteinizing hormone) and FSH (follicle-stimulating hormone) in the presence of low circulating concentrations of sex steroids. IGD is associated with a normal sense of smell (normosmic IGD) in approximately 40% of affected individuals and an impaired sense of smell (Kallmann syndrome) in approximately 60%. IGD can first become apparent in infancy, adolescence, or adulthood. Infant boys with congenital IGD often have micropenis and cryptorchidism. Adolescents and adults with IGD have clinical evidence of hypogonadism and incomplete sexual maturation on physical examination. Adult males with IGD tend to have prepubertal testicular volume (i.e., <4 mL), absence of secondary sexual features (e.g., facial and axillary hair growth, deepening of the voice), decreased muscle mass, diminished libido, erectile dysfunction, and infertility. Adult females have little or no breast development and primary amenorrhea. Although skeletal maturation is delayed, the rate of linear growth is usually normal except for the absence of a distinct pubertal growth spurt.
Hypogonadotropic hypogonadism 7 with or without anosmia
MedGen UID:
82883
Concept ID:
C0271623
Disease or Syndrome
Isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD) is characterized by inappropriately low serum concentrations of the gonadotropins LH (luteinizing hormone) and FSH (follicle-stimulating hormone) in the presence of low circulating concentrations of sex steroids. IGD is associated with a normal sense of smell (normosmic IGD) in approximately 40% of affected individuals and an impaired sense of smell (Kallmann syndrome) in approximately 60%. IGD can first become apparent in infancy, adolescence, or adulthood. Infant boys with congenital IGD often have micropenis and cryptorchidism. Adolescents and adults with IGD have clinical evidence of hypogonadism and incomplete sexual maturation on physical examination. Adult males with IGD tend to have prepubertal testicular volume (i.e., <4 mL), absence of secondary sexual features (e.g., facial and axillary hair growth, deepening of the voice), decreased muscle mass, diminished libido, erectile dysfunction, and infertility. Adult females have little or no breast development and primary amenorrhea. Although skeletal maturation is delayed, the rate of linear growth is usually normal except for the absence of a distinct pubertal growth spurt.
Liver Cirrhosis
MedGen UID:
7368
Concept ID:
C0023890
Disease or Syndrome
Cirrhosis is scarring of the liver. Scar tissue forms because of injury or long-term disease. Scar tissue cannot do what healthy liver tissue does - make protein, help fight infections, clean the blood, help digest food and store energy. Cirrhosis can lead to . -Easy bruising or bleeding, or nosebleeds. -Swelling of the abdomen or legs . -Extra sensitivity to medicines. -High blood pressure in the vein entering the liver. -Enlarged veins called varices in the esophagus and stomach. Varices can bleed suddenly. - Kidney failure. -Jaundice. -Severe itching. -Gallstones. A small number of people with cirrhosis get liver cancer. Your doctor will diagnose cirrhosis with blood tests, imaging tests, or a biopsy. Cirrhosis has many causes. In the United States, the most common causes are chronic alcoholism and hepatitis. Nothing will make the scar tissue disappear, but treating the cause can keep it from getting worse. If too much scar tissue forms, you may need to consider a liver transplant. . NIH: National Institute of Diabetes and Digestive and Kidney Diseases.
Elevated hepatic transaminases
MedGen UID:
338525
Concept ID:
C1848701
Finding
Elevations of the levels of SGOT and SGPT in the serum. SGOT (serum glutamic oxaloacetic transaminase) and SGPT (serum glutamic pyruvic transaminase) are transaminases primarily found in the liver and heart and are released into the bloodstream as the result of liver or heart damage. SGOT and SGPT are used clinically mainly as markers of liver damage.
Hypogonadotropic hypogonadism 7 with or without anosmia
MedGen UID:
82883
Concept ID:
C0271623
Disease or Syndrome
Isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD) is characterized by inappropriately low serum concentrations of the gonadotropins LH (luteinizing hormone) and FSH (follicle-stimulating hormone) in the presence of low circulating concentrations of sex steroids. IGD is associated with a normal sense of smell (normosmic IGD) in approximately 40% of affected individuals and an impaired sense of smell (Kallmann syndrome) in approximately 60%. IGD can first become apparent in infancy, adolescence, or adulthood. Infant boys with congenital IGD often have micropenis and cryptorchidism. Adolescents and adults with IGD have clinical evidence of hypogonadism and incomplete sexual maturation on physical examination. Adult males with IGD tend to have prepubertal testicular volume (i.e., <4 mL), absence of secondary sexual features (e.g., facial and axillary hair growth, deepening of the voice), decreased muscle mass, diminished libido, erectile dysfunction, and infertility. Adult females have little or no breast development and primary amenorrhea. Although skeletal maturation is delayed, the rate of linear growth is usually normal except for the absence of a distinct pubertal growth spurt.
Increased serum ferritin
MedGen UID:
69130
Concept ID:
C0241013
Finding
Abnormal raised concentration of ferritin, a ubiquitous intracellular protein that stores iron, in the blood.
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.
Hypogonadotropic hypogonadism 7 with or without anosmia
MedGen UID:
82883
Concept ID:
C0271623
Disease or Syndrome
Isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD) is characterized by inappropriately low serum concentrations of the gonadotropins LH (luteinizing hormone) and FSH (follicle-stimulating hormone) in the presence of low circulating concentrations of sex steroids. IGD is associated with a normal sense of smell (normosmic IGD) in approximately 40% of affected individuals and an impaired sense of smell (Kallmann syndrome) in approximately 60%. IGD can first become apparent in infancy, adolescence, or adulthood. Infant boys with congenital IGD often have micropenis and cryptorchidism. Adolescents and adults with IGD have clinical evidence of hypogonadism and incomplete sexual maturation on physical examination. Adult males with IGD tend to have prepubertal testicular volume (i.e., <4 mL), absence of secondary sexual features (e.g., facial and axillary hair growth, deepening of the voice), decreased muscle mass, diminished libido, erectile dysfunction, and infertility. Adult females have little or no breast development and primary amenorrhea. Although skeletal maturation is delayed, the rate of linear growth is usually normal except for the absence of a distinct pubertal growth spurt.

Term Hierarchy

Follow this link to review classifications for Hemochromatosis type 3 in Orphanet.

Recent clinical studies

Etiology

Papanikolaou G, Politou M, Roetto A, Bosio S, Sakelaropoulos N, Camaschella C, Loukopoulos D
Blood Cells Mol Dis 2001 Jul-Aug;27(4):744-9. doi: 10.1006/bcmd.2001.0444. PMID: 11778658

Diagnosis

Roetto A, Daraio F, Alberti F, Porporato P, Calì A, De Gobbi M, Camaschella C
Blood Cells Mol Dis 2002 Nov-Dec;29(3):465-70. PMID: 12547237
Roetto A, Totaro A, Piperno A, Piga A, Longo F, Garozzo G, Calì A, De Gobbi M, Gasparini P, Camaschella C
Blood 2001 May 1;97(9):2555-60. PMID: 11313241

Prognosis

Ponka P
Semin Hematol 2002 Oct;39(4):249-62. PMID: 12382200

Clinical prediction guides

Calzolari A, Oliviero I, Deaglio S, Mariani G, Biffoni M, Sposi NM, Malavasi F, Peschle C, Testa U
Blood Cells Mol Dis 2007 Jul-Aug;39(1):82-91. Epub 2007 Apr 10 doi: 10.1016/j.bcmd.2007.02.003. PMID: 17428703
Frank J, Poblete-Gutiérrez P, Weiskirchen R, Gressner O, Merk HF, Lammert F
Physiol Res 2006;55 Suppl 2:S75-83. PMID: 17298224
Ponka P
Semin Hematol 2002 Oct;39(4):249-62. PMID: 12382200
Papanikolaou G, Politou M, Roetto A, Bosio S, Sakelaropoulos N, Camaschella C, Loukopoulos D
Blood Cells Mol Dis 2001 Jul-Aug;27(4):744-9. doi: 10.1006/bcmd.2001.0444. PMID: 11778658

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