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{{Fanconi anemia}}
{{Fanconi anemia}}


{{CMG}}
{{CMG}} {{AE}} {{shyam}}


{{SK}} Fanconi anaemia
{{SK}} Fanconi anaemia; Fanconi hypoplastic anemia; Fanconi panmyelopathy; Fanconi pancytopenia; FA


==Overview==
==[[Fanconi anemia overview|Overview]]==
==[[Fanconi anemia historical perspective|Historical Perspective]]==


==Causes==
==[[Fanconi anemia classification|Classification]]==


==Hematological Abnormalities==
==[[Fanconi anemia pathophysiology|Pathophysiology]]==


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.
==[[Fanconi anemia causes|Causes]]==
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===
==[[Fanconi anemia differential diagnosis|Differentiating Fanconi Anemia from Other Diseases]]==


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.
==[[Fanconi anemia epidemiology and demographics|Epidemiology and Demographics]]==


===Acute Myeloid Leukemia===
==[[Fanconi anemia risk factors|Risk Factors]]==


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.
==[[Fanconi anemia screening|Screening]]==
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===
==[[Fanconi anemia natural history, complications and prognosis|Natural History, Complications and Prognosis]]==


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%.
== [[Fanconi anemia history and symptoms|History and Symptoms]] ==
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==
== [[Fanconi anemia physical examination|Physical Examination]] ==


==Diagnosis==
== [[Fanconi anemia laboratory findings|Laboratory Findings]] ==
'''Patient#1'''
<gallery>
Image:


Fanconi's anemia 001.jpg
== [[Fanconi anemia electrocardiogram|Electrocardiogram]] ==


Image:
== [[Fanconi anemia x ray|X Ray]] ==


Fanconi's anemia 002.jpg
== [[Fanconi anemia medical therapy|Medical Therapy]] ==


</gallery>
== [[Fanconi anemia surgery|Surgery]] ==


'''Patient #2'''
== [[Fanconi anemia primary prevention|Primary Prevention]] ==


<gallery>
== [[Fanconi anemia secondary prevention|Secondary Prevention]] ==


Fanconi's anemia 101.jpg
== [[Fanconi anemia cost-effectiveness of therapy|Cost-Effectiveness of Therapy]] ==


</gallery>
== [[Fanconi anemia future or investigational therapies|Future or Investigational Therapies]] ==


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


==References==
==References==
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[[Category:Disease]]
[[Category:Disease]]
[[Category:Mature chapter]]
[[Category:Mature chapter]]
<references />

Latest revision as of 16:39, 5 May 2019

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Shyam Patel [2]

Synonyms and keywords: Fanconi anaemia; Fanconi hypoplastic anemia; Fanconi panmyelopathy; Fanconi pancytopenia; FA

Overview

Historical Perspective

Classification

Pathophysiology

Causes

Differentiating Fanconi Anemia from Other Diseases

Epidemiology and Demographics

Risk Factors

Screening

Natural History, Complications and Prognosis

History and Symptoms

Physical Examination

Laboratory Findings

Electrocardiogram

X Ray

Medical Therapy

Surgery

Primary Prevention

Secondary Prevention

Cost-Effectiveness of Therapy

Future or Investigational Therapies

References

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