Fanconi anemia natural history, complications and prognosis
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Overview
Complications
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.
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.[1] 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]
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.[3] 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.[4] 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.
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.
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.
References
- ↑ Alter BP (2014). "Fanconi anemia and the development of leukemia". Best Pract Res Clin Haematol. 27 (3–4): 214–21. doi:10.1016/j.beha.2014.10.002. PMC 4254647. PMID 25455269.
- ↑ Alter BP, Rosenberg PS, Brody LC (2007). "Clinical and molecular features associated with biallelic mutations in FANCD1/BRCA2". J Med Genet. 44 (1): 1–9. doi:10.1136/jmg.2006.043257. PMC 2597904. PMID 16825431.
- ↑ Tönnies H, Huber S, Kuhl JS, Gerlach A, Ebell W, Neitzel H (2003). "Clonal chromosomal aberrations in bone marrow cells of Fanconi anemia patients: gains of the chromosomal segment 3q26q29 as an adverse risk factor". Blood. 101 (10): 3872–4. doi:10.1182/blood-2002-10-3243. PMID 12511406.
- ↑ Kutler DI, Singh B, Satagopan J, Batish SD, Berwick M, Giampietro PF; et al. (2003). "A 20-year perspective on the International Fanconi Anemia Registry (IFAR)". Blood. 101 (4): 1249–56. doi:10.1182/blood-2002-07-2170. PMID 12393516.