View source for Fanconi anemia

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{{DiseaseDisorder infobox |
  Name           = Fanconi Anemia |
  ICD10          = {{ICD10|D|61|0|d|60}} |
  ICD9           = {{ICD9|284.0}} |
  ICDO           = |
  Image          = |
  Caption        = |
  OMIM           = 227650 |
  OMIM_mult      = |
  MedlinePlus    = 000334 |
  DiseasesDB     = 4745 |
}}
{{Fanconi anemia}}

{{CMG}}

{{SK}} Fanconi anaemia

==Overview==

==Causes==

==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.

===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.

===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 factor]]s, 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==

==Diagnosis==
'''Patient#1'''
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'''Patient #2'''

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==See also==
*[[Absent radius]]

==References==
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International Fanconi Anemia Registry study. Blood 1994;84:1650-1655.
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* Auerbach AD, Allen RG. Leukemia and preleukemia in Fanconi anemia patients. A review of the literature and report of the International Fanconi Anemia Registry. Cancer Genet.Cytogenet. 1991;51:1-12.
* 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.
* Gluckman E, Auerbach AD, Horowitz MM et al. Bone marrow transplantation for Fanconi anemia. Blood 1995;86:2856-2862.
* Gluckman E. Radiosensitivity in Fanconi anemia: application to the conditioning for bone marrow transplantation. Radiother.Oncol. 1990;18 Suppl 1:88-93.
* Cipolleschi MG, Dello SP, Olivotto M. The role of hypoxia in the maintenance of hematopoietic stem cells. Blood 1993;82:2031-2037.
* Zhang X, Li J, Sejas DP, Pang Q. Hypoxia-reoxygenation induces premature senescence in FA bone marrow hematopoietic cells. Blood 2005
* 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.
* 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.
* Pagano G, Youssoufian H. Fanconi anaemia proteins: major roles in cell protection against oxidative damage. Bioessays 2003;25:589-595.
* 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.
* 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.
* Meetei AR, de Winter JP, Medhurst AL et al. A novel ubiquitin ligase is deficient in Fanconi anemia. Nat.Genet. 2003;35:165-170.
* Vandenberg CJ, Gergely F, Ong CY et al. BRCA1-independent ubiquitination of FANCD2. Mol.Cell 2003;12:247-254.
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* 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.
* 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.
* 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.
* Taniguchi T, Garcia-Higuera I, Xu B et al. Convergence of the fanconi anemia and ataxia telangiectasia signaling pathways. Cell 2002;109:459-472.
* 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.
* 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.
* 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.
* 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.
* 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.
* 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.
* 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.
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{{Hematology}}

[[ca:Anèmia de Fanconi]]
[[de:Fanconi-Anämie]]
[[es:Anemia de Fanconi]]
[[fr:Anémie de Fanconi]]
[[hu:Fanconi anémia]]
[[nl:Fanconi-anemie]]
[[fi:Fanconin anemia]]

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