Fanconi anemia natural history, complications and prognosis
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Shyam Patel [2]
Overview
The natural history of Fanconi anemia involves progressive bone marrow failure, which can result in clinical manifestations such as fatigue, infections, and bleeding. Complications of Fanconi anemia include cardiovascular failure, iron overload from frequent transfusions, myelodysplastic syndrome, acute myeloid leukemia, overt bone marrow failure. The prognosis of Fanconi anemia is poor in the absence of allogeneic stem cell transplant. The prognosis is especially poor if Fanconi anemia evolves into acute myeloid leukemia. After allogeneic transplant, however, the prognosis can be quite favorable and cure can be achieved.
Natural History
The natural history of Fanconi anemia involves progressive bone marrow failure, which can result in clinical manifestations such as fatigue, infections, and bleeding. The diagnosis of Fanconi anemia is typically made during childhood, with a median age of diagnosis of 7-8 years. However, decreased blood counts can remain undetectable for many years due to the insidious natural history of the disease.[1] The natural history involves a gradual reduction in the hematopoietic stem cell pool.[1] Children will usually present with signs and symptoms of bone marrow failure. These signs and symptoms include:
- Fatigue: Severe fatigue can arise in the setting of low hemoglobin levels. In some cases, transfusion of packed red blood cells may be required.
- Infections: In some cases, significant infections can occur in patients with Fanconi anemia. This is a result of low white blood cell counts. The spectrum of infections can encompass bacterial, viral, or fungal organisms. Patients may need antibiotics, antiviral, or antifungal medications.
- Bleeding: In some cases, bleeding and bruising can occur, which is a result of low platelet counts. Patients may need platelet transfusions if clinically significant bleeding occurs.
Complications
The complications of Fanconi anemia range from iron overload, which can be readily treated, to the development of acute leukemia, which can be fatal. Complications include overt bone marrow failure, myelodysplastic syndrome, acute myeloid leukemia, and iron overload from frequent transfusions. The complications can be broadly divided into systemic complications and bone marrow-related complications.
Systemic complications
- Cardiovascular collapse: This refers to failure of the heart to produce a sufficient blood pressure to maintain normal homeostasis and oxygen delivery. This can lead to death from hypoxia and hypoxemia within a short period of time. The reason for this is severely decreased hemoglobin concentration, which results in impaired ability of the heart to meet the oxygen demands of peripheral tissue.
- Exacerbation of cardiopulmonary conditions: Fanconi anemia can result in high-output cardiac failure, which refers to the inability of the circulatory system to meet the demands of exercising tissue, despite a high cardiac output. Fanconi anemia can also exacerbate lung disease, since the capillary beds in the pulmonary circulation function to load oxygen onto hemoglobin for delivery to tissue beds.
- Exacerbation of neurologic conditions: Fanconi anemia can contribute to cerebrovascular disease, or strokes, since the brain requires oxygen for survival of neurons.
- Myocardial infarction: Myocardial infarction, or heart attack, occurs if the anemia is severe such that the oxygen-carrying capacity is reduced to the coronary tissue. For this reason, patients with coronary artery disease should be transfused packed red blood cells if hemoglobin is less than 8 g/dl, compared to the conventional threshold of 7 g/dl for the general population.
- Transfusion dependence: This occurs when a patient requires repeated transfusions with packed red blood cells in order to maintain hemoglobin within an acceptable range, such as greater than 7 g/dl. Complications of transfusion include:
- Transfusion-associated circulatory overload (TACO)[2] For this reason, a restricted transfusion strategy is preferred over a liberal strategy.[3]
- Transfusion-related acute lung injury (TRALI)[2]
- Iron overload, or hemosiderosis: After frequent transfusions of packed red blood cells, patients can develop iron deposition in the skin, liver, pancreas, heart, and metacarpophalangeal joints. In some cases, iron chelation therapy may be needed.
- Transfusion reaction due to ABO blood group incompatibility
- Myelodysplastic syndrome: Myelodysplastic syndrome, formerly known as pre-leukemia, is a condition in which immature myeloid cells in the bone marrow cannot differentiate into functional cell types. Myelodysplastic syndrome shares many of the morphologic features of AML with some important differences. First, the percentage of undifferentiated progenitor cells, blasts cells, is always less than 20% (based on World Health Organization classification of myeloid neoplasms) 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.[4] 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.[5]
- Acute myeloid leukemia: Patients with Fanconi anemia also have elevated risks of developing AML, defined as presence of 20% or more of myeloid blasts in the BM, 20% or more of myeloid blasts in the peripheral blood, or presence of characteristic chromosomal rearrangements that typically define AML. All of the subtypes of AML can occur in FA with the exception of promyelocytic. However, myelomonocytic (French-American-British (FAB) M4 group) and acute monocytic (FAB M5 group) 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.[6] This is due to clonal evolution, which has been well-described over the recent years. 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/AML related causes within 2 years.
- Overt 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.[7] 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%.
Prognosis
The prognosis of Fanconi anemia is variable and develops upon the complications that arise. The median survival of patients with FA was 21 years of age prior to the 21st century. Currently, however, the prognosis is significant improved, given advances in therapeutics and reduction in the risk of death due to bleeding or infectious complications. Bone marrow failure can often be cured by allogeneic stem cell transplant. However, many patients eventually develop acute myelogenous leukemia (AML), and prognosis can be quite poor. 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.[8] 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).[9] 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
- ↑ 1.0 1.1 Nalepa G, Clapp DW (2014). "Fanconi anemia and the cell cycle: new perspectives on aneuploidy". F1000Prime Rep. 6: 23. doi:10.12703/P6-23. PMC 3974572. PMID 24765528.
- ↑ 2.0 2.1 Sahu S, Verma A (2014). "Adverse events related to blood transfusion". Indian J Anaesth. 58 (5): 543–51. doi:10.4103/0019-5049.144650. PMC 4260299. PMID 25535415.
- ↑ Holst LB, Petersen MW, Haase N, Perner A, Wetterslev J (2015). "Restrictive versus liberal transfusion strategy for red blood cell transfusion: systematic review of randomised trials with meta-analysis and trial sequential analysis". BMJ. 350: h1354. doi:10.1136/bmj.h1354. PMC 4372223. PMID 25805204. Review in: Evid Based Med. 2015 Oct;20(5):170
- ↑ 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.
- ↑ 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.
- ↑ Shimamura A, Alter BP (2010). "Pathophysiology and management of inherited bone marrow failure syndromes". Blood Rev. 24 (3): 101–22. doi:10.1016/j.blre.2010.03.002. PMC 3733544. PMID 20417588.