Última actualización:
June 30, 2016
Años publicados: 2010, 2016
NORD gratefully acknowledges Alex Knisely, MD, Institute of Liver Studies/Histopathology, King’s College Hospital, London, UK, for assistance in the preparation of this report.
Atransferrinemia is an extremely rare genetic disorder characterized by low levels of healthy, functional red cells in the blood (hypochromic, microcytic anemia) and by the accumulation of excess iron in the body (hemosiderosis). Symptoms may vary based upon the severity of anemia and upon the extent of iron accumulation in the body and the specific organs affected. Common symptoms include recurrent infections and growth delays. Atransferrinemia is principally caused by mutations of the transferrin (TF) gene and is inherited as an autosomal recessive trait. Atransferrinemia is classified as an iron overload disorder. A milder form of atransferrinemia, known as hypotransferrinemia, is caused by mutations in the same gene.
The symptoms and severity of atransferrinemia vary from one person to another depending upon the specific location and extent of iron accumulation in the body. Some individuals may develop mild symptoms, others may develop serious, life-threatening complications.
Affected individuals often develop severe microcytic hypochromic anemia, a condition characterized by abnormally small red cells (erythrocytes) that are insufficiently filled with hemoglobin. Red cells are blood cells that deliver oxygen throughout the body. Hemoglobin is the iron-rich, oxygen-bearing protein in blood. Microcytic hypochromic anemia may be associated with pallor and fatigue. Some affected individuals may have a slightly enlarged liver (hepatomegaly).
Atransferrinemia is also often associated with growth delays and recurrent infections. Additional symptoms depend upon the location and extent of iron accumulation in the body. Atransferrinemia can potentially affect the liver, heart, joints, pancreas, kidneys and thyroid. Iron accumulation can damage affected organs and can cause scarring (cirrhosis) of the liver, arthritis, an underactive thyroid (hypothyroidism) and heart abnormalities. In severe cases, affected individuals can develop life-threatening complications such as pneumonia or an impaired ability to circulate blood to the lungs and the rest of the body, resulting in fluid buildup in the heart, lungs and various body tissues (congestive heart failure).
Atransferrinemia / hypotransferrinemia is principally caused by mutations of the transferrin (TF) gene. It is inherited as an autosomal recessive trait. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.
Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents both to pass the defective gene and, therefore, to have an affected child is 25 percent with each pregnancy. The risk to have a child who is a carrier like the parents is 50 percent with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25 percent. The risk is the same for males and females.
Investigators have determined that the transferrin (TF) gene is located at band 21 on the long arm (q) of chromosome 3 (3q21). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 3q21” refers to band 21 on the long arm of chromosome 3. The numbered bands help to specify the location of the thousands of genes that are present on each chromosome.
The TF gene contains instructions for producing a protein called transferrin. This protein is essential for the proper transport of iron within the body. Mutations of the TF gene result in deficient levels of functional transferrin, which ultimately results in the accumulation of excess iron in various organs of the body. Iron accumulation damages the tissue of affected organs, causing the characteristic symptoms of atransferrinemia.
Researchers have determined that the absence of transferrin results in an inability of the body to deliver iron to immature red cells in the bone marrow. The lack of delivery of iron to these immature cells causes the body to increase the absorption of iron in the intestines significantly, resulting in the iron overload that characterizes atransferrinemia.
Atransferrinemia is an extremely rare disorder. Approximately 10 cases in 8 families have been reported in the medical literature. Because atransferrinemia may go unrecognized or misdiagnosed, determining its true frequency in the general population is difficult. Atransferrinemia affects males and females in equal numbers. Atransferrinemia was first described in the medical literature in 1961.
A diagnosis of atransferrinemia is made based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Laboratory tests can reveal low or undetectable levels of transferrin in the blood.
Treatment
The treatment of atransferrinemia is directed toward the specific symptoms that are apparent in each individual. Affected individuals have been treated with infusions of plasma or of a urified form of transferrin (apotransferrin) that may correct certain symptoms (e.g., anemia, growth deficiencies) associated with the disorder. As the liver synthesizes most transferrin, liver transplantation theoretically could supply a cure; its use has not been reported. In long-term survival with atransferrinemia, iron toxicity to tissues, rather than anemia, is the principal cause of illness. Approaches to off-loading excess body iron stores are not well worked out (see below).
Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.
Iron chelators are drugs that are often used to treat other disorders of iron overload. Iron chelators bind to the excess iron in the body allowing it to be dissolved in water and excreted from the body through the kidneys. The role, if any, that iron chelators may play in the treatment of individuals with atransferrinemia is unknown. For the possible use of liver transplantation, see “Treatment”, above.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
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For information about clinical trials sponsored by private sources, contact:
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For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
TEXTBOOKS
Rimoin D, Connor JM, Pyeritz RP, Korf BR, eds. Emery and Rimoin’s Principles and Practice of Medical Genetics. 5th ed. Churchill Livingstone. New York, NY; 2007:2390-2391.
JOURNAL ARTICLES
Beaumont-Epinette MP, Delobel JB, Ropert M, et al. Hereditary hypotransferrinemia can lead to elevated transferrin saturation and, when associated to HFE or HAMP mutations, to iron overload. Blood Cells Mol Dis. 2015 Feb;54(2):151-4. doi: 10.1016/j.bcmd.2014.11.020. Epub 2014 Nov 26.
Chen C, Wen S, Tan X. Molecular analysis of a novel case of congenital atransferrinemia. Acta Haematol. 2009;122:27-28.
Aslan D, Crain K, Beutler E. A new case of human atransferrinemia with a previously undescribed mutation in the transferrin gene. Acta Haematol. 2007;118:244-247.
Wallace DF, Subramaniam VN. Non-HFE hemochromatosis. World J Gastroenterol. 2007;13:4690-4698.
Knisely AS, Gelbart T, Beutler E. Molecular characterization of a third case of human atransferrinemia. Blood. 2004;104:2607.
Ponka P. Rare cases of hereditary iron overload. Semin Hematol. 2002;39:249-262.
Beutler E, Gelbart T, Lee G, et al. Molecular characterization of a case of atransferrinemia. Am Soc Hematol. 2000;96:4071-4074.
Hamill RL, Woods JC, Cook BA. Congenital atransferrinemia. A case report and review of the literature. J Clin Pathol. 1991;96:215-218.
INTERNET
McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No: 209300; Last Update: 10/05/2015. Available at: https://omim.org/entry/209300. Accessed June 28, 2016.
Orphanet Encyclopedia. Congenital atransferrinemia. November 2013. Available at: https://www.orpha.net/consor/cgi-bin/Disease_Search.php?lng=EN&data_id=795&Disease_Disease_Search_diseaseGroup=Atransferrinemia&Disease_Disease_Search_diseaseType=Pat&Disease(s)/group%20of%20diseases=Congenital-atransferrinemia&title=Congenital-atransferrinemia&search=Disease_Search_Simple. Accessed June 28, 2016.
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The Genetic and Rare Diseases Information Center (GARD) has information and resources for patients, caregivers, and families that may be helpful before and after diagnosis of this condition. GARD is a program of the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH).
View reportOrphanet has a summary about this condition that may include information on the diagnosis, care, and treatment as well as other resources. Some of the information and resources are available in languages other than English. The summary may include medical terms, so we encourage you to share and discuss this information with your doctor. Orphanet is the French National Institute for Health and Medical Research and the Health Programme of the European Union.
View reportOnline Mendelian Inheritance In Man (OMIM) has a summary of published research about this condition and includes references from the medical literature. The summary contains medical and scientific terms, so we encourage you to share and discuss this information with your doctor. OMIM is authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine.
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