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Encyclopedia > Fanconi anemia
Fanconi Anemia
Classification & external resources
ICD-10 D61.0
ICD-9 284.0
OMIM 227650
DiseasesDB 4745
MedlinePlus 000334
eMedicine ped/3022 

Fanconi anemia (FA) is a genetic disease that affects children and adults from all ethnic backgrounds. Named for the Swiss pediatrician who originally described this disorder, Guido Fanconi, FA is characterized by short stature, skeletal anomalies, increased incidence of solid tumors and leukemias, bone marrow failure (aplastic anemia), and cellular sensitivity to DNA damaging agents such as mitomycin C. The International Statistical Classification of Diseases and Related Health Problems (most commonly known by the abbreviation ICD) provides codes to classify diseases and a wide variety of signs, symptoms, abnormal findings, complaints, social circumstances and external causes of injury or disease. ... The following codes are used with International Statistical Classification of Diseases and Related Health Problems. ... // C00-D48 - Neoplasms (C00-C14) Malignant neoplasms, lip, oral cavity and pharynx (C00) Malignant neoplasm of lip (C01) Malignant neoplasm of base of tongue (C02) Malignant neoplasm of other and unspecified parts of tongue (C03) Malignant neoplasm of gum (C04) Malignant neoplasm of floor of mouth (C05) Malignant neoplasm of... The International Statistical Classification of Diseases and Related Health Problems (most commonly known by the abbreviation ICD) provides codes to classify diseases and a wide variety of signs, symptoms, abnormal findings, complaints, social circumstances and external causes of injury or disease. ... The following is a list of codes for International Statistical Classification of Diseases and Related Health Problems. ... The Mendelian Inheritance in Man project is a database that catalogues all the known diseases with a genetic component, and - when possible - links them to the relevant genes in the human genome. ... The Disease Bold textDatabase is a free website that provides information about the relationships between medical conditions, symptoms, and medications. ... MedlinePlus (medlineplus. ... eMedicine is an online clinical medical knowledge base that was founded in 1996. ... Guido Fanconi was a Swiss pediatrician. ... Aplastic anemia is a condition where bone marrow does not produce sufficient new cells to replenish blood cells. ... Mitomycin or mitomycin C is a form of chemotherapy given intravenously to treat upper gastro-intestinal (e. ...

Contents

Causes

FA is primarily an autosomal recessive genetic condition. There are at least 12 genes for which mutations are known to cause FA: A, B, C, D1, D2, E, F, G, I, J, L, and M. FANCB is the one exception to FA being autosomal recessive, as this gene is on the X chromosome. For an autosomal recessive disorder, both parents must be carriers in order for a child to inherit the condition. If both parents are carriers, there is a 25% risk with each pregnancy for the mother to have an affected child. Approximately 1,000 persons worldwide presently suffer from the disease. The carrier frequency in the Ashkenazi Jewish population is about 1/90. Genetic counseling and genetic testing is recommended for families that may be carriers of Fanconi anemia. Image File history File links Autorecessive-3. ... Image File history File links Autorecessive-3. ... An autosome is a non-sex chromosome. ... In genetics, the term recessive gene refers to an allele that causes a phenotype (visible or detectable characteristic) that is only seen in a homozygous genotype (an organism that has two copies of the same allele). ... Genetic counseling is the process by which patients or relatives, at risk of an inherited disorder, are advised of the consequences and nature of the disorder, the probability of developing or transmitting it, and the options open to them in management and family planning in order to prevent, avoid or... Genetic testing allows the genetic diagnosis of vulnerabilities to inherited diseases, and can also be used to determine a persons ancestry. ...


Because of the failure of the components of the blood - white and red blood cells and platelets - the body cannot successfully combat infection, fatigue, spontaneous hemorrhage or bleeding. Bone marrow transplantation is the accepted treatment to repair the hematological problems associated with FA. However, even with a bone marrow transplant, patients face an increased risk of acquiring cancer and other serious health problems throughout their lifetime.


Prognosis

Many patients eventually develop acute myelogenous leukemia (AML). Older patients are extremely likely to develop head and neck, esophageal, gastrointestinal, vulvar and anal cancers. Patients who have had a successful bone marrow transplant and, thus, are cured of the blood problem associated with FA still must have regular examinations to watch for signs of cancer. Many patients do not reach adulthood. Acute myelogenous leukemia (AML), also known as acute myeloid leukemia, is a cancer of the myeloid line of blood cells. ...


The overarching medical challenge that Fanconi patients face is a failure of their bone marrow to produce blood cells. In addition, Fanconi patients normally are born with a variety of birth defects. For instance, 90% of the Jewish children born with Fanconi's have no thumbs. A good number of Fanconi patients have kidney problems, trouble with their eyes, developmental retardation and other serious defects, such as microcephaly (small head).


Quality, comprehensive care is available for treating Fanconi anemia. Since research is on-going, there is hope that as knowledge gained through clinical trials and research grows, a cure may be developed.


Hematological Abnormalities

Clinically, haematological abnormalities are the most serious symptoms in FA. By the age of 40, 98% of FA will have developed some type of haematologic abnormality. It is interesting to note however the few cases in which older patients have died without ever developing them. Symptoms appear progressively and often lead to complete bone marrow (BM) failure. While at birth blood count is usually normal, macrocytosis/megaloblastic anemia, defined as unusually large red blood cells, is the first detected abnormality, often within the first decade of life (median age of onset is 7 years). Within the next 10 years, over 50% of patients presenting haematological abnormalities will have developed pancytopenia, defined as abnormalities in two or more blood cell lineage. Indeed, thrombocytopenia, defined as platelet count of less than 100x109/L precede neutropenia, defined as a neutrophil count below 1x109/L, both appearing with relative equal frequencies, causing hemorrhage and increases in recurrent infections. As FA is now known to affect the DNA repair and given the current knowledge about dynamic cell division in the BM, it is not surprising to find out that patients are more likely to develop BM failure, myelodysplastic syndromes(MDS) and acute myeloid leukemia (AML). The next sections will detail those pathologies. Grays Anatomy illustration of cells in bone marrow. ... Macrocytosis is the enlargement of red blood cells with near-constant haemoglobin concentration, and is defined by a mean corpuscular volume (MCV) of greater than 100 femtolitres (the precise criterion varies between laboratories). ... Megaloblastic anemia is an anemia (of macrocytic classification) which results from a deficiency of vitamin B12 and folic acid. ... Pancytopenia is a medical condition in which there is a reduction in the number of red and white blood cells, as well as platelets. ... Thrombocytopenia (or -paenia, or thrombopenia in short) is the presence of relatively few platelets in blood. ... A 250 ml bag of newly collected platelets. ... It has been suggested that Agranulocytosis be merged into this article or section. ... Neutrophil granulocytes (commonly referred to as neutrophils) are a class of white blood cells and are part of the immune system. ... To meet Wikipedias quality standards, this article or section may require cleanup. ... Infection is also the title of an episode of the television series Babylon 5; see Infection (Babylon 5). ... The structure of part of a DNA double helix Deoxyribonucleic acid (DNA) is a nucleic acid that contains the genetic instructions for the development and function of living organisms. ... Acute myeloid leukemia (AML), which is also known as acute myelogenous leukemia, is a cancer of the myeloid line of white blood cells, characterized by the rapid proliferation of abnormal cells which accumulate in the bone marrow and interfere with the production of normal blood cells. ...


Myelodysplastic Syndromes

MDS, formerly known as pre-leukemia, are a group of BM neoplastic diseases that share many of the morphologic features of AML with some important differences. First, the percentage of undifferentiated progenitor cells, blasts cells, is always less than 30% and there is considerably more dysplasia, defined as cytoplasmic and nuclear morphologic changes in erythroid, granulocytic and megakaryocytic precursors, than what is usually seen in cases of AML. These changes reflect delayed apoptosis or a failure of programmed cell death. When left untreated, MDS can lead to AML in about 30% of cases. Due the nature of the FA pathology, MDS diagnosis cannot be made solely through cytogenic analysis of the BM. Indeed, it is only when morphologic analysis of BM cells is performed, that a diagnosis of MDS can be ascertained. Upon examination, MDS-afflicted FA patients will show many clonal variations, appearing either prior or subsequent to the MDS. Furthermore, cells will show chromosomal aberrations, the most frequent being monosomy 7 and partial trisomies of chromosome 3q 15. Observation of monosomy 7 within the BM is well correlated with an increased risk of developing AML and with a very poor prognosis, death generally ensuing within 2 years 2.

Image File history File links No higher resolution available. ... This Manual of Style has the simple purpose of making things easy to read by following a consistent format — it is a style guide. ...

Acute Myeloid Leukemia

As stated earlier, FA patients also have elevated risks of developing AML, defined as presence of 30% or more of myeloid blasts in the BM or 5 to 20% myeloid blasts in the blood. All of the subtypes of AML can occur in FA with the exception of promyelocytic. However, myelomonocytic and acute monocytic are the most common subtypes observed. It is also interesting to note that many MDS patients will evolve into AML given they survive long enough. Furthermore, the risk of developing AML increases with the onset of BM failure. While the risk of developing either MDS or AML before the age of 20 is only 27%, this risk increases to 43% by the age of 30 and 52% by the age of 40. Even with BM transplant, about one fourth of patients will die from MDS/ALS related causes within 2 years.


Bone Marrow Failure

The last major haematological complication associated with FA is BM failure, defined as inadequate blood cell production. Several types of BM failure are observed in FA patients and are generally precede MDS and AML. Detection of decreasing blood count is generally the first sign used to assess necessity of treatment and possible BM transplant. While most FA patients are initially responsive to androgen therapy and haemopoietic growth factors, these have been shown to promote leukemia, especially in patients with clonal cytogenic abnormalities, and have severe side effects, including hepatic adenomas and adenocarcinomas. The only treatment left would be BM transplant; however, such an operation has a relatively low success rate in FA patients when the donor is unrelated (30% 5-year survival) 16. It is therefore imperative to transplant from HLA-identical sibling. Furthermore, due to the increased susceptibility of FA patients to chromosomal damage, pre-transplant conditioning cannot include high doses of radiations or immunosuppressants, and thus increase chances of patients developing graft-versus-host disease. If all precautions are taken, and the BM transplant is performed within the first decade of life, 2-year probability of survival can be as high as 89%. However, if the transplant is performed at ages older than 10, 2-year survival rates drop to 54%. A recent report by Zhang et al investigates the mechanism of BM failure in FANCC-/- cells. They hypothesize and successfully demonstrate that continuous cycles of hypoxia-reoxygenation, such as those seen by haemopoietic and progenitor cells as they migrate between hyperoxic blood and hypoxic BM tissues, leads to premature cellular senescence and therefore inhibition of BM haemopoietic function. Senescence, together with apoptosis, may constitute a major mechanism of haemopoietic cell depletion occurred in BM failure.


Molecular Basis of FA

Due to the similarities in the phenotypes of the different FA complementation groups, it was reasonable to assume that all affected genes interacted in a common pathway. Up until the late 90s, nothing was known about the proteins encoded by FA genes. However, more recently, studies have shown that five of these proteins, FANCA, -C, -E, -F and –G assemble to form a core protein complex in the cytoplasm that is then translocated into the nucleus by ways of nuclear localization signals on FANCA and FANCE. Assembly is thought to be activated by DNA damage due to cross-linking agents or reactive oxygen species (ROS). Indeed, FANCA and FANCG have been observed to multimerize when a cell is faced with oxidative stress-induced damage. Furthermore, the complex assembling is thought to require FANCB and BRCA1, however, the existence of FANCB protein has never been confirmed and opponents of this theory point out similarities in FANCB and BRCA-2 localization and function. Following assembly, the protein core complex activates FANCL protein which acts as an E3 ubiquitin-ligase and monoubiquitinates FANCD2. It was previously thought that BRCA1, with its zinc finger ubiquitin ligase domain was responsible for the post-transcriptional modification of FANCD2, however, this has since been invalidated and BRCA1 interaction with the FA protein complex is still being investigated. Ubiquinated FANCD2, also know as FANCD2-L, then goes on to interact with a BRCA1/BRCA2 complex. Again, details of this interaction have yet to be discovered. However, it is already known that similar complexes are involved in genome surveillance and associated with a variety of proteins implicated in DNA repair and chromosomal stability. With a crippling mutation in any FA protein in the complex, DNA repair has been shown to be much less effective, as can be seen from the damage caused by cross-linking agents such as cisplatin, diepoxybutane and Mitomycin C. It follows that tissues, as is the case in bone marrow, in which successful cell replication is vital, will be severely affected by FA protein dysfunction where FA leads to decreased haemopoiesis and bone marrow failure due to progenitor and stem cell senescence. In another pathway responding to ionizing radiation, FANCD2 is thought to be phosphorylated by protein complex ATM/ATR activated by double-strand DNA breaks, and takes part in S-phase checkpoint control. This pathway was proven by the presence of radioresistant DNA synthesis, the hallmark of a defect in the S phase checkpoint, in patients with FA-D1 or FA-D2. Such a defect readily leads to uncontrollable replication of cells and might also explain the increase frequency of AML in these patients.


Other FA protein interactions

Although the above described pathway seems to be the most integral part of the DNA damage response in cells and explains the pathology of FA, novel approaches have determined that most FA proteins have an alternate role. Indeed, recent investigations on FANCC, one of the intensively studied proteins, have shown that it plays an important role in cellular responses to oxidative stress. For example, it has been found to interact with NADPH cytochrome P450 reductase, associated with increased production of ROS, and glutathione S-transferase, responsible for production of the anti-oxidant glutathione. These two enzymes are both involved in either triggering or detoxifying ROS. Not surprisingly, mice with Cu/Zn superoxide dismutase and FANCC mutations demonstrate defective haemopoiesis. FANCC was also shown to bind STAT1 and help receptor docking and phosphorylation of STAT135, which helps in tumor suppression. This leads to the conclusion that FANCC participates in cell growth arrest and cell cycle progression, inhibiting apoptosis, a possible cause of bone marrow failure due to depletion of haemopoietic progenitors. Another FA protein linked to protection against oxidative damage is FANCG. Indeed, this protein interacts with cytochrome P450 2E1 suggesting a possible role in detoxifying cytochrome ROS, produced readily by the members of this superfamily36. Furthermore, FANCG is identical to post-replication repair protein XRCC9, hinting at the possibility that FANCG also interacts directly with DNA by means of its internal leucine zipper. Thus it is readily seen that FA proteins also acts outside of the Fanconi pathway, either by helping neutralize ROS or by taking part in DNA repair. Such mechanisms help understand the causes behind bone marrow failure, where reoxygenation-induced oxidative stress is very common19. Furthermore, it is known that cross-linking agents produce ROS and it is possible that FA cell hypersensitivity to cross-linkers is not due directly to them, but rather to the cell’s impaired ability to cope with increased ROS production.


See also

Absent radius is a very rare medical condition in which the radius bone is not developed. ...

References

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2. Tischkowitz M, Dokal I. Fanconi anaemia and leukaemia - clinical and molecular aspects. Br.J.Haematol. 2004;126:176-191.


3. Lensch MW, Rathbun RK, Olson SB, Jones GR, Bagby GC, Jr. Selective pressure as an essential force in molecular evolution of myeloid leukemic clones: a view from the window of Fanconi anemia. Leukemia 1999;13:1784-1789.


4. Kutler DI, Auerbach AD. Fanconi anemia in Ashkenazi Jews. Fam.Cancer 2004;3:241-248.


5. Rosendorff J, Bernstein R, Macdougall L, Jenkins T. Fanconi anemia: another disease of unusually high prevalence in the Afrikaans population of South Africa. Am.J.Med.Genet. 1987;27:793-797.


6. Howlett NG, Taniguchi T, Olson S et al. Biallelic inactivation of BRCA2 in Fanconi anemia. Science 2002;297:606-609.


7. Joenje H, Patel KJ. The emerging genetic and molecular basis of Fanconi anaemia. Nat.Rev.Genet. 2001;2:446-457.


8. Auerbach AD, Rogatko A, Schroeder-Kurth TM. International Fanconi Anemia Registry: relation of clinical symptoms to diepoxybutane sensitivity. Blood 1989;73:391-396.


9. Dokal I. The genetics of Fanconi's anaemia. Baillieres Best.Pract.Res.Clin.Haematol. 2000;13:407-425.


10. Kutler DI, Singh B, Satagopan J et al. A 20-year perspective on the International Fanconi Anemia Registry (IFAR). Blood 2003;101:1249-1256.


11. Alter BP. Cancer in Fanconi anemia, 1927-2001. Cancer 2003;97:425-440.


12. Butturini A, Gale RP, Verlander PC et al. Hematologic abnormalities in Fanconi anemia: an International Fanconi Anemia Registry study. Blood 1994;84:1650-1655.


13. Alter BP, Caruso JP, Drachtman RA et al. Fanconi anemia: myelodysplasia as a predictor of outcome. Cancer Genet.Cytogenet. 2000;117:125-131.


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15. Tonnies H, Huber S, Kuhl JS et al. Clonal chromosomal aberrations in bone marrow cells of Fanconi anemia patients: gains of the chromosomal segment 3q26q29 as an adverse risk factor. Blood 2003;101:3872-3874.


16. Gluckman E, Auerbach AD, Horowitz MM et al. Bone marrow transplantation for Fanconi anemia. Blood 1995;86:2856-2862.


17. Gluckman E. Radiosensitivity in Fanconi anemia: application to the conditioning for bone marrow transplantation. Radiother.Oncol. 1990;18 Suppl 1:88-93.


18. Cipolleschi MG, Dello SP, Olivotto M. The role of hypoxia in the maintenance of hematopoietic stem cells. Blood 1993;82:2031-2037.


19. Zhang X, Li J, Sejas DP, Pang Q. Hypoxia-reoxygenation induces premature senescence in FA bone marrow hematopoietic cells. Blood 2005


20. Naf D, Kupfer GM, Suliman A, Lambert K, D'Andrea AD. Functional activity of the fanconi anemia protein FAA requires FAC binding and nuclear localization. Mol.Cell Biol. 1998;18:5952-5960.


21. de Winter JP, Leveille F, van Berkel CG et al. Isolation of a cDNA representing the Fanconi anemia complementation group E gene. Am.J.Hum.Genet. 2000;67:1306-1308.


22. Pagano G, Youssoufian H. Fanconi anaemia proteins: major roles in cell protection against oxidative damage. Bioessays 2003;25:589-595.


23. Park SJ, Ciccone SL, Beck BD et al. Oxidative stress/damage induces multimerization and interaction of Fanconi anemia proteins. J.Biol.Chem. 2004;279:30053-30059.


24. Connor F, Bertwistle D, Mee PJ et al. Tumorigenesis and a DNA repair defect in mice with a truncating Brca2 mutation. Nat.Genet. 1997;17:423-430.


25. Meetei AR, de Winter JP, Medhurst AL et al. A novel ubiquitin ligase is deficient in Fanconi anemia. Nat.Genet. 2003;35:165-170.


26. Vandenberg CJ, Gergely F, Ong CY et al. BRCA1-independent ubiquitination of FANCD2. Mol.Cell 2003;12:247-254.


27. D'Andrea AD, Dahl N, Guinan EC, Shimamura A. Marrow failure. Hematology.(Am.Soc.Hematol.Educ.Program.) 200258-72.


28. Garcia-Higuera I, Taniguchi T, Ganesan S et al. Interaction of the Fanconi anemia proteins and BRCA1 in a common pathway. Mol.Cell 2001;7:249-262.


29. Wang Y, Cortez D, Yazdi P et al. BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures. Genes Dev. 2000;14:927-939.


30. Cortez D, Wang Y, Qin J, Elledge SJ. Requirement of ATM-dependent phosphorylation of brca1 in the DNA damage response to double-strand breaks. Science 1999;286:1162-1166.


31. Taniguchi T, Garcia-Higuera I, Xu B et al. Convergence of the fanconi anemia and ataxia telangiectasia signaling pathways. Cell 2002;109:459-472.


32. Kruyt FA, Hoshino T, Liu JM et al. Abnormal microsomal detoxification implicated in Fanconi anemia group C by interaction of the FAC protein with NADPH cytochrome P450 reductase. Blood 1998;92:3050-3056.


33. Cumming RC, Lightfoot J, Beard K et al. Fanconi anemia group C protein prevents apoptosis in hematopoietic cells through redox regulation of GSTP1. Nat.Med. 2001;7:814-820.


34. Hadjur S, Ung K, Wadsworth L et al. Defective hematopoiesis and hepatic steatosis in mice with combined deficiencies of the genes encoding Fancc and Cu/Zn superoxide dismutase. Blood 2001;98:1003-1011.


35. Pang Q, Fagerlie S, Christianson TA et al. The Fanconi anemia protein FANCC binds to and facilitates the activation of STAT1 by gamma interferon and hematopoietic growth factors. Mol.Cell Biol. 2000;20:4724-4735.


36. Futaki M, Igarashi T, Watanabe S et al. The FANCG Fanconi anemia protein interacts with CYP2E1: possible role in protection against oxidative DNA damage. Carcinogenesis 2002;23:67-72.


37. de Winter JP, Waisfisz Q, Rooimans MA et al. The Fanconi anaemia group G gene FANCG is identical with XRCC9. Nat.Genet. 1998;20:281-283.


38. Clarke AA, Philpott NJ, Gordon-Smith EC, Rutherford TR. The sensitivity of Fanconi anaemia group C cells to apoptosis induced by mitomycin C is due to oxygen radical generation, not DNA crosslinking. Br.J.Haematol. 1997;96:240-247.


External links


  Results from FactBites:
 
AllRefer Health - Fanconi's Anemia (Anemia - Fanconi's, FA) (402 words)
Fanconi's anemia is an inherited disease that primarily affects the bone marrow, resulting in decreased production of all types of blood cells.
Fanconi's anemia is distinct from Fanconi's syndrome, a rare kidney disorder in which nutrients are lost through the urine.
Fanconi's anemia is inherited in an autosomal recessive fashion, thus one copy of an abnormal gene is passed on by each parent.
Fanconi anemia - Wikipedia, the free encyclopedia (411 words)
Fanconi anemia (FA) is a rare genetic disease that affects children and adults from all ethnic backgrounds.
Named for the Swiss pediatrician who originally described this disorder, Guido Fanconi, FA is characterized by short stature, skeletal anomalies, increased incidence of solid tumors and leukemias, bone marrow failure (aplastic anemia), and cellular sensitivity to DNA damaging agents such as mitomycin C.
In addition, Fanconi patients normally are born with a variety of birth defects.
  More results at FactBites »

 
 

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