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Hemochromatosis type 2A(HFE2A)

MedGen UID:
356321
Concept ID:
C1865614
Disease or Syndrome
Synonyms: HFE2A; HJV (HFE2)-Related Juvenile Hemochromatosis
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: HPO
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).
 
Gene (location): HFE2 (1q21.1)
OMIM®: 602390

Disease characteristics

Excerpted from the GeneReview: Juvenile Hereditary Hemochromatosis
Juvenile hemochromatosis is characterized by onset of severe iron overload occurring typically in the first to third decades of life. Males and females are equally affected. Prominent clinical features include hypogonadotropic hypogonadism, cardiomyopathy, arthropathy, and liver fibrosis or cirrhosis. Hepatocellular cancer has not been reported. The main cause of death is cardiac disease. If juvenile hemochromatosis is detected early enough and if blood is removed regularly through the process of phlebotomy to achieve iron depletion, morbidity and mortality are greatly reduced.  [from GeneReviews]
Authors:
Y Paul Goldberg   view full author information

Additional descriptions

From OMIM
Juvenile, or type 2, hemochromatosis is an autosomal recessive inborn error of iron metabolism that leads to severe iron loading and organ failure before 30 years of age (summary by Roetto et al., 1999). The common complications of iron overload, including liver cirrhosis, cardiac disease, endocrine failure, diabetes, arthropathy, and skin pigmentation, are similar to those of adult-onset hereditary hemochromatosis, but hypogonadism and cardiomyopathy are the most common symptoms at presentation. Heart failure and/or major arrhythmias are usually the cause of death in the absence of treatment. Early detection of the disorder is important because iron depletion by phlebotomy can prevent organ damage and all disease manifestations. Hemochromatosis type 2A (HFE2A) is caused by mutation in the hemojuvelin gene (HJV; 608374) on chromosome 1q21. Genetic Heterogeneity of Hemochromatosis Type 2 Hemochromatosis type 2B (HFE2B; 613313) is caused by mutation in the hepcidin gene (HAMP; 606464) on chromosome 19q13.  http://www.omim.org/entry/602390
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.  http://ghr.nlm.nih.gov/condition/hereditary-hemochromatosis

Clinical features

Cardiomyopathy
MedGen UID:
209232
Concept ID:
C0878544
Disease or Syndrome
Cardiomyopathy is the name for diseases of the heart muscle. These diseases enlarge your heart muscle or make it thicker and more rigid than normal. In rare cases, scar tissue replaces the muscle tissue. Some people live long, healthy lives with cardiomyopathy. Some people don't even realize they have it. In others, however, it can make the heart less able to pump blood through the body. This can cause serious complications, including . - Heart failure . - Abnormal heart rhythms . - Heart valve problems. - Sudden cardiac arrest. Heart attacks, high blood pressure, infections, and other diseases can all cause cardiomyopathy. Some types of cardiomyopathy run in families. In many people, however, the cause is unknown. Treatment might involve medicines, surgery, other medical procedures, and lifestyle changes. . NIH: National Heart, Lung, and Blood Institute.
Hypogonadotropic hypogonadism 7 with or without anosmia
MedGen UID:
82883
Concept ID:
C0271623
Disease or Syndrome
Congenital idiopathic hypogonadotropic hypogonadism (IHH) is a disorder characterized by absent or incomplete sexual maturation by the age of 18 years, in conjunction with low levels of circulating gonadotropins and testosterone and no other abnormalities of the hypothalamic-pituitary axis. Idiopathic hypogonadotropic hypogonadism can be caused by an isolated defect in gonadotropin-releasing hormone (GNRH; 152760) release, action, or both. Other associated nonreproductive phenotypes, such as anosmia, cleft palate, and sensorineural hearing loss, occur with variable frequency. In the presence of anosmia, idiopathic hypogonadotropic hypogonadism has been called 'Kallmann syndrome (KS),' whereas in the presence of a normal sense of smell, it has been termed 'normosmic idiopathic hypogonadotropic hypogonadism (nIHH)' (summary by Raivio et al., 2007). Because families have been found to segregate both KS and nIHH, the disorder is here referred to as 'hypogonadotropic hypogonadism with or without anosmia (HH).' For a discussion of genetic heterogeneity of hypogonadotropic hypogonadism with or without anosmia, see 147950.
Hypogonadotropic hypogonadism 7 with or without anosmia
MedGen UID:
82883
Concept ID:
C0271623
Disease or Syndrome
Congenital idiopathic hypogonadotropic hypogonadism (IHH) is a disorder characterized by absent or incomplete sexual maturation by the age of 18 years, in conjunction with low levels of circulating gonadotropins and testosterone and no other abnormalities of the hypothalamic-pituitary axis. Idiopathic hypogonadotropic hypogonadism can be caused by an isolated defect in gonadotropin-releasing hormone (GNRH; 152760) release, action, or both. Other associated nonreproductive phenotypes, such as anosmia, cleft palate, and sensorineural hearing loss, occur with variable frequency. In the presence of anosmia, idiopathic hypogonadotropic hypogonadism has been called 'Kallmann syndrome (KS),' whereas in the presence of a normal sense of smell, it has been termed 'normosmic idiopathic hypogonadotropic hypogonadism (nIHH)' (summary by Raivio et al., 2007). Because families have been found to segregate both KS and nIHH, the disorder is here referred to as 'hypogonadotropic hypogonadism with or without anosmia (HH).' For a discussion of genetic heterogeneity of hypogonadotropic hypogonadism with or without anosmia, see 147950.
Hepatomegaly
MedGen UID:
42428
Concept ID:
C0019209
Sign or Symptom
Enlargement of the liver.
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.
Increased serum iron
MedGen UID:
57739
Concept ID:
C0151900
Finding
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
MedGen UID:
57992
Concept ID:
C0162834
Pathologic Function
A darkening of the skin related to an increase in melanin production and deposition.

Recent clinical studies

Etiology

Cunat S, Giansily-Blaizot M, Bismuth M, Blanc F, Dereure O, Larrey D, Quellec AL, Pouderoux P, Rose C, Raingeard I, Renard E, Schved JF, Aguilar-Martinez P; CHU Montpellier AOI 2004 Working Group
Clin Chem 2007 Dec;53(12):2060-9. Epub 2007 Oct 19 doi: 10.1373/clinchem.2007.090605. [Epub ahead of print] PMID: 17951290
Le Gac G, Scotet V, Ka C, Gourlaouen I, Bryckaert L, Jacolot S, Mura C, Férec C
Hum Mol Genet 2004 Sep 1;13(17):1913-8. Epub 2004 Jul 14 doi: 10.1093/hmg/ddh206. [Epub ahead of print] PMID: 15254010

Diagnosis

Pellicelli AM, Morrone A, Barbieri L, Andreoli A
Ann Hepatol 2012 Nov-Dec;11(6):951-4. PMID: 23109461
Zhang AS, West AP Jr, Wyman AE, Bjorkman PJ, Enns CA
J Biol Chem 2005 Oct 7;280(40):33885-94. Epub 2005 Aug 15 doi: 10.1074/jbc.M506207200. [Epub ahead of print] PMID: 16103117
Kaufman HW, Strom CM
MLO Med Lab Obs 2003 Jul;35(7):30-2, 36, 38 passim. PMID: 12889228

Therapy

Pellicelli AM, Morrone A, Barbieri L, Andreoli A
Ann Hepatol 2012 Nov-Dec;11(6):951-4. PMID: 23109461

Clinical prediction guides

Pellicelli AM, Morrone A, Barbieri L, Andreoli A
Ann Hepatol 2012 Nov-Dec;11(6):951-4. PMID: 23109461
Le Gac G, Scotet V, Ka C, Gourlaouen I, Bryckaert L, Jacolot S, Mura C, Férec C
Hum Mol Genet 2004 Sep 1;13(17):1913-8. Epub 2004 Jul 14 doi: 10.1093/hmg/ddh206. [Epub ahead of print] PMID: 15254010

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