NORD gratefully acknowledges Hannah Llorin, MS, NORD Editorial Intern from the Stanford University MS Program in Human Genetics and Genetic Counseling and Hannah Wand, MS, CGC, Clinical Instructor (Affiliated), Dept of Pediatrics, Division of Medical Genetics, Stanford University, for assistance in the preparation of this report.
Juvenile hemochromatosis is a rare genetic disorder characterized by the accumulation of iron in various organs of the body. Symptoms usually become apparent before the age of 30, though they may appear at a later age in some individuals. The specific symptoms and severity of juvenile hemochromatosis vary from one person to another. Common symptoms include absent or decreased function of the testes in males or ovaries in females (hypogonadotropic hypogonadism), heart (cardiac) disease, scarring of the liver (cirrhosis), joint disease, diabetes and dark discoloration of patches of skin (hyperpigmentation). If untreated, juvenile hemochromatosis can potentially cause life-threatening complications. Juvenile hemochromatosis is caused by mutations in one of two genes (HJV and HAMP). Juvenile hemochromatosis is inherited in an autosomal recessive manner.
Symptoms of juvenile hemochromatosis resemble those seen in the more common HFE-related hemochromatosis, also called classic hereditary hemochromatosis. However, juvenile hemochromatosis is a separate, distinct disorder that occurs at an earlier age and is typically more severe than HFE-related hemochromatosis.
The symptoms and severity of juvenile hemochromatosis can vary from one person to another, even within the same family. Major symptoms include hypogonadotropic hypogonadism and heart, liver and joint disease. In some patients, nonspecific, vague symptoms may precede the development of more serious complications. These earlier symptoms may include fatigue, joint pain (arthralgia) and lack of appetite. If left untreated, juvenile hemochromatosis can cause serious, life-threatening complications.
The symptoms of juvenile hemochromatosis usually become apparent at some point before 30 years of age. However, in rare cases, some individuals have not developed symptoms until their 30s.
Hypogonadotropic hypogonadism is characterized by absent or decreased function of the testes in males or ovaries in females. Hypogonadotropic hypogonadism can result in delays in puberty, loss of sexual hair, impotence in men (erectile dysfunction) and a reduction or absence of the menstrual cycle for six months in girls who have already started menstruation (secondary amenorrhea). Lack of a sex drive and infertility may also be associated with this condition. Prolonged hypogonadism can result in low bone density (osteopenia) and fragile bones that are prone to fracture (osteoporosis).
Heart abnormalities can develop in individuals with juvenile hemochromatosis. Many individuals with juvenile hemochromatosis develop disease of the heart muscle (cardiomyopathy), irregular heartbeats (arrhythmias) and/or heart failure. Proper treatment can prevent the development of heart disease or improve heart health; however, without proper iron removal treatment, sudden death due to heart abnormalities can occur. In some patients, heart disease may be the first noticeable sign of juvenile hemochromatosis.
Additional symptoms associated with juvenile hemochromatosis include a progressive darkening of patches of skin (skin hyperpigmentation), joint pain (arthralgia) and liver disease, eventually resulting in enlargement of the liver (hepatomegaly) and scarring (cirrhosis).
Patients with juvenile hemochromatosis can also have diabetes. Diabetes is a common disorder in which the body does not produce enough or is unable to properly use insulin. The most obvious symptoms are unusually excessive thirst and urination. Uncontrolled diabetes can lead to serious health complications such as heart disease. Individuals will need to be treated for diabetes independent of their treatment for juvenile hemochromatosis.
Rarely, affected individuals may experience an underactive thyroid (hypothyroidism) or inadequate production of the steroid hormones cortisol and aldosterone (adrenocortical insufficiency).
Juvenile hemochromatosis is a genetic condition inherited in an autosomal recessive manner. Juvenile hemochromatosis is caused by mutations in HJV and HAMP. Individuals have two copies of the HJV gene and the HAMP gene, one copy from the sperm and one copy from the egg. Juvenile hemochromatosis type 2A occurs when a child inherits two altered (or mutated) copies of HJV, and therefore has no normal copy of the gene. Juvenile hemochromatosis type 2A is more common, accounting for 90 percent of known cases of juvenile hemochromatosis. Juvenile hemochromatosis type 2B occurs when a child has two altered copies of HAMP.
The parents of a child with juvenile hemochromatosis are carriers, meaning that they have one altered copy and one normal copy of a gene associated with juvenile hemochromatosis. Carriers do not show symptoms of juvenile hemochromatosis but can have children with juvenile hemochromatosis. The risk for two carrier parents to both pass the altered copy of the gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive normal copies of the gene from both parents is 25%. The risk is the same for males and females.
The HJV gene contains instructions for creating a protein known as hemojuvelin. The HAMP gene contains instructions for creating a protein known as hepcidin. Researchers believe that these proteins are essential for the proper absorption and transport of iron within the body. Mutations of these genes result in deficient levels of functional hemojuvelin or hepcidin, which ultimately results in the accumulation of iron in the liver, heart and pancreas. Iron accumulation damages the tissue of affected organs causing the characteristic symptoms of juvenile hemochromatosis.
Most researchers think that mutations in genes associated with juvenile hemochromatosis are 100% penetrant, which means that individuals who have two altered copies of the gene will have some degree of disease. Some researchers also suspect that additional, as yet unidentified, genetic and possibly environmental factors influence the development and progression of juvenile hemochromatosis in each individual.
Juvenile hemochromatosis affects males and females in equal numbers. The disorder is rare, but the actual incidence in the general population is unknown. Juvenile hemochromatosis has been reported worldwide. The disorder typically becomes apparent between 10-30 years of age. Mutations of the HJV gene account for the majority (~90%) of cases of juvenile hemochromatosis.
Early diagnosis and prompt treatment of juvenile hemochromatosis are essential and may help to prevent permanent organ damage and potentially life-threatening complications resulting from excessive iron storage. The disorder may be diagnosed based upon a thorough clinical evaluation; detection of certain physical findings (including hepatomegaly, diabetes mellitus, abnormal skin pigmentation, heart disease, hypogonadism, and/or arthritis), a thorough patient history; a complete family history and specialized tests.
When juvenile hemochromatosis is suspected, blood tests are performed to measure the blood levels of iron and an iron compound that is used as an indicator of the body’s iron stores (serum ferritin levels). Blood tests can also detect increased transferrin saturation. Transferrin is a protein involved in the transport of iron from the intestine into the bloodstream.
In addition, specialized imaging tests such as magnetic resonance imaging (MRI) may reveal increased density of the liver due to iron accumulation. A MRI uses a magnetic field and radio waves to provide detailed images of certain organs and tissues. A liver biopsy may also be used to aid in diagnosing juvenile hemochromatosis. During a liver biopsy, samples of liver tissue are removed and microscopically examined to detect increased iron storage and the presence of scarring (cirrhosis).
A diagnosis of juvenile hemochromatosis can be confirmed through genetic testing, which can reveal mutations of the HJV or HAMP genes that cause the disorder. Molecular genetic testing is available on a clinical basis.
The treatment of juvenile hemochromatosis is directed toward the specific symptoms that are apparent in each individual. Treatment is generally similar to existing treatment options for HFE-related hemochromatosis (classic hereditary hemochromatosis) Detailed treatment recommendations have been published by the American College of Gastroenterology (see Kowdley 2019) and American Association for the Study of Liver Diseases (see Bacon 2011). The main treatment for juvenile hemochromatosis is the removal of excess iron from the body through a procedure called phlebotomy.
Much of the iron in the body is present in red blood cells. Therefore, therapy involves the regular removal of blood via a vein (phlebotomy) to reduce excess iron from within the body. Phlebotomy may be required about once or twice a week. Weekly phlebotomy may continue to be necessary for approximately two to three years because individuals with juvenile hemochromatosis usually experience severe iron overload. Once acceptable levels of iron are achieved, weekly phlebotomy therapy is stopped and maintenance therapy is started. With maintenance therapy, individuals give blood (to reduce iron levels) less frequently than every week. The specific amount required varies, but generally, four to six phlebotomies per year are sufficient.
Iron chelators are another method for treating iron overload. Iron chelators are drugs that bind to the excess iron in the body allowing it to be dissolved in water and excreted from the body through the kidneys. Deferoxamine is an iron chelator that has been used as an adjunct therapy in individuals with juvenile hemochromatosis who also have anemia or severe cardiac disease.
Early, prompt detection and treatment of juvenile hemochromatosis are essential because it can prevent organ damage and the development of certain secondary complications like heart failure. Individuals that are diagnosed early in childhood and placed on and stick to phlebotomy programs have a significantly reduced development of secondary complications. Some damage, once it occurs, is irreversible. Secondary complications that do develop are treated by standard, conventional methods.
Hypogonadotropic hypogonadism can be treated with hormone replacement therapy. Joint pain may be treated with non-steroidal anti-inflammatories (NSAIDs). Heart disease is treated with angiotensin-converting enzyme (ACE) inhibitors, drugs that help remove salt and water from the body (diuretics [water pills]) and drugs called glycosides that are commonly used to treat heart failure and arrhythmias. In some patients, severe, irreversible heart damage has necessitated a heart transplant.
Early signs of liver disease such as (fibrosis) can be treated with phlebotomy. In some individuals with classic hereditary hemochromatosis, these symptoms have been reversible. It is not known whether these symptoms are reversible in individuals with juvenile hemochromatosis. Liver cirrhosis is not reversible and requires therapy with propranolol and nadolol, medications that prevent high blood pressure in the main artery of the liver (portal hypertension). In some patients, a liver transplant may become necessary.
Genetic counseling is recommended for affected individuals and their families. Other treatment is offered based on an individual’s symptoms.
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Takami A, et al. Juvenile hemochromatosis: a case report and review of the literature. Pharmaceuticals 2021; 13.8:195.
Kowdley KV, et al. ACG clinical guideline: hereditary hemochromatosis. American Journal of Gastroenterology 2019; 114.8:1202-1218. https://journals.lww.com/ajg/fulltext/2019/08000/acg_clinical_guideline__hereditary_hemochromatosis.11.aspx
Kong X, et al. Genotypic and phenotypic spectra of hemojuvelin mutations in primary hemochromatosis patients: a systematic review. Orphanet Journal of Rare Diseases 2019;14.1:171.
Brissot P, et al. Haemochromatosis. Nature Reviews Disease Primers 4.1 2018: 1-15.
Porto, Graça, et al. EMQN best practice guidelines for the molecular genetic diagnosis of hereditary hemochromatosis (HH). European Journal of Human Genetics 2016; 24.4: 479-495.
Bacon BR, et al. Diagnosis and management of hemochromatosis: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatology 2011;54.1: 328.
Wallace DF, Subramaniam VN. Non-HFE haemochromatosis. World J Gastro. 2007;13:4690-4698.
Fabio G, Minonzio F, Delbini P, Bianchi A, Cappellini MD. Reversal of cardiac complications by deferiprone and deferiprone and defoxamine combination therapy in a patient affected by a severe type of juvenile hemochromatosis (JH). Blood. 2007;109:362-364.
Franchini M. Hereditary iron overload: update and pathophysiology, diagnosis and treatment. Am J Hematol. 2006;81:202-209.
Rivard SR, Lanzara C, Grimard D. Juvenile hemochromatosis locus maps to chromosome 1q in a French Canadian population. Eur J Hum Genet. 2003;11:585-589.
Camaschella C, Roetto A, de Gobbi M. Juvenile hemochromatosis. Semin Hematol. 2002;39:242-248.
Camaschella C, Roetto A, Cicilano M, et al. Juvenile and adult hemochromatosis are distinct genetic disorders. Eur J Hum Genet. 1997;5:371-375.
Piperno A, Bertola F, Bentivegna A. Juvenile Hemochromatosis. 2005 Feb 17 [Updated 2020 Jan 9]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2021. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1170/ Accessed May 4, 2021.
McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:602390; Last Update: 06/20/2018. Available at: https://www.omim.org/entry/602390 Accessed May 4, 2021.
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