Fanconi anemia

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Synonyms and keywords: Fanconi anaemia

Overview

Causes

Hematological Abnormalities

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 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

Diagnosis

Patient#1

Patient #2

See also

References

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