| Fanconi anemia | |
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| Fanconi anemia has anautosomal recessive pattern of inheritance. | |
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| Specialty | Hematology  |
Fanconi anemia (FA), also known asFanconi cancer, is a rare,autosomal recessivegenetic disease characterized byaplastic anemia,congenital defects,endocrinological abnormalities, and an increased incidence of developingcancer. The study of Fanconi anemia has improved scientific understanding of the mechanisms of normal bone marrow function and the development of cancer. Among those affected, the majority developcancer, most oftenacute myelogenous leukemia (AML),myelodysplastic syndrome (MDS), and liver cancer. 90% developaplastic anemia (the inability to produce blood cells) by age 40. About 60–75% havecongenital defects, commonlyshort stature, abnormalities of the skin, arms, head, eyes, kidneys, and ears, and developmental disabilities. Around 75% have some form ofendocrine problem, with varying degrees of severity. 60% of FA is FANC-A, 16q24.3, which has a later onset of bone marrow failure.
FA is the result of a genetic defect in a cluster of proteins responsible forDNA repair viahomologous recombination.[1] The well-known cancer susceptibility genesBRCA1 andBRCA2 are also examples of FA genes (FANCS and FANCD1 respectively), and biallelicmutation of any of the two genes usually results in anembryonically lethal outcome, and should the proband come to term, experience a severe form of Fanconi anemia.
Treatment with androgens and hematopoietic (blood cell) growth factors can help bone marrow failure temporarily, but the long-term treatment isbone marrow transplant if a donor is available.[2] Because of the genetic defect in DNA repair, cells from people with FA are sensitive to drugs that treat cancer byDNA crosslinking, such asmitomycin C. The typical age of death was 30 years in 2000.[2]
FA occurs in about one per 130,000 live births, with a higher frequency inAshkenazi Jews andAfrikaners in South Africa.[3] The disease is named after the Swiss pediatrician who originally described this disorder,Guido Fanconi.[4][5] Some forms of Fanconi anemia, such as those of complementation group D1, N, and S, are embryonically lethal in most cases, which might account for the rare observation of these complementation groups. It should not be confused withFanconi syndrome, akidney disorder also named after Dr. Fanconi.
FA is characterized by bone marrow failure,AML, solid tumors, and developmental abnormalities. Classic features include abnormal thumbs, absent radii, short stature, skin hyperpigmentation, includingcafé au lait spots, abnormal facial features (triangular face, microcephaly), abnormal kidneys, and decreased fertility. Many FA patients (about 30%) do not have any of the classic physical findings, but diepoxybutane chromosome fragility assay, showing increased chromosomal breaks, can make the diagnosis.[6] About 80% of FA will develop bone marrow failure by age 20.[citation needed]
The first sign of a hematologic problem is usuallypetechiae and bruises, with later onset ofpale appearance,feeling tired, and infections. Because macrocytosis usually precedes alow platelet count, patients with typical congenital anomalies associated with FA should be evaluated for an elevatedred blood cellmean corpuscular volume.[7]
FA is primarily anautosomalrecessive genetic disorder. This means that two mutatedalleles (one from each parent) are required to cause the disease. The risk is 25% that each subsequent child will have FA. About 2% of FA cases are X-linked recessive, which means that if the mother carries one mutated Fanconi anemia allele on oneX chromosome, a 50% chance exists that male offspring will present with Fanconi anemia.[citation needed]
Scientists have identified 21 FA or FA-like genes:FANCA,FANCB,FANCC,FANCD1 (BRCA2),FANCD2,FANCE,FANCF,FANCG,FANCI,FANCJ (BRIP1),FANCL,FANCM,FANCN (PALB2),FANCO (RAD51C),FANCP (SLX4),FANCQ (XPF),FANCS (BRCA1), FANCT (UBE2T),FANCU (XRCC2),FANCV (REV7), andFANCW (RFWD3).FANCBis the one exception to FA beingautosomal recessive, as this gene is on the X chromosome. These genes are involved in DNA repair.[citation needed]
The carrierfrequency in the Ashkenazi Jewish population is about one in 90.[8]Genetic counseling andgenetic testing are recommended for families who may becarriers of Fanconi anemia.[citation needed]
Because of the failure of hematologic components—white blood cells,red blood cells, andplatelets—to develop, the body's capabilities tofight infection, deliver oxygen, andform clots are all diminished.[citation needed]
Clinically, hematological abnormalities are the most serious symptoms of FA. By the age of 40, 98% of FA patients will have developed some type ofhematological abnormality. However, a few cases have occurred in which older patients have died without ever developing them. Symptoms appear progressively and often lead to completebone marrow 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 developedpancytopenia, defined as abnormalities in two or more blood cell lineages. This is in contrast toDiamond–Blackfan anemia, which affects only erythrocytes, andShwachman–Diamond syndrome, which primarily causes neutropenia. Most commonly, a low platelet count (thrombocytopenia) precedes a low neutrophil count (neutropenia), with both appearing with relatively equal frequencies. The deficiencies cause an increased risk ofhemorrhage and recurrentinfections, respectively.[citation needed]
As FA is now known to affect DNA repair, specificallyhomologous recombination,[1] and given the current knowledge about dynamic cell division in the bone marrow, patients are consequently more likely to develop bone marrow failure,myelodysplastic syndromes, andacute myeloid leukemia (AML).[citation needed]
MDSs, formerly known as preleukemia, are a group of bone marrow neoplastic diseases that share many of the morphologic features of AML, with some important differences. First, the percentage of undifferentiated progenitor cells,blast cells, is always less than 20%, with considerably moredysplasia, defined as cytoplasmic and nuclear morphologic changes inerythroid,granulocytic, andmegakaryocytic precursors, than what is usually seen in cases of AML. These changes reflect delayedapoptosis or a failure ofprogrammed cell death. When left untreated, MDS can lead to AML in about 30% of cases. Due to the nature of the FA pathology, MDS diagnosis cannot be made solely through cytogenetic analysis of the marrow. Indeed, it is only when morphologic analysis of marrow cells is performed that a diagnosis of MDS can be ascertained. Upon examination, MDS-affected FA patients will show many clonal variations, appearing either prior to or subsequent to the MDS. Furthermore, cells will show chromosomal aberrations, the most frequent beingmonosomy 7 and partialtrisomies ofchromosome 3q 15. Observation of monosomy 7 within the marrow is well correlated with an increased risk of developing AML and with a very poor prognosis, death generally ensuing within 2 years (unless promptallogeneichematopoietic progenitor cell transplant is an option).[9]
FA patients are at elevated risk for the development of AML, defined as the presence of 20% or more of myeloid blasts in the marrow or 5 to 20% myeloid blasts in the blood. All of the subtypes of AML can occur in FA, except for promyelocytic. However, myelomonocytic and acute monocytic are the most common subtypes observed. Many MDS patients' diseases evolve into AML if they survive long enough. Furthermore, the risk of developing AML increases with the onset of bone marrow failure.[citation needed]
Although 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. Historically, even with a marrow transplant, about a quarter of FA patients diagnosed with MDS/ALS have died from MDS/ALS-related causes within two years,[10] although more recent published evidence suggests that earlierallogeneichematopoietic progenitor cell transplantation in children with FA is leading to better outcomes over time.[11]
The last major haematological complication associated with FA is bone marrow failure, defined as inadequate blood cell production. Several types of failure are observed in FA patients and generally precede MDS and AML. Detection of decreasing blood count is generally the first sign used to assess the necessity of treatment and possible transplant. While most FA patients are initially responsive to androgen therapy and haemopoieticgrowth factors, these have been shown to promote leukemia, especially in patients with clonal cytogenetic abnormalities, and have severe side effects, includinghepatic adenomas andadenocarcinomas. The only treatment left would be a bone marrow transplant; however, such an operation has a relatively low success rate in FA patients when the donor is unrelated (30% 5-year survival). It is, therefore, imperative to transplant from an HLA-identical sibling. Furthermore, due to the increased susceptibility of FA patients to chromosomal damage, pretransplant conditioning cannot include high doses of radiation or immunosuppressants, thus increasing the chances of patients developinggraft-versus-host disease. If all precautions are taken and the marrow transplant is performed within the first decade of life, a two-year probability of survival can be as high as 89%. However, if the transplant is performed at ages older than 10, two-year survival rates drop to 54%.[citation needed]
A recent report by Zhang et al. investigates the mechanism of bone marrow failure in FANCC-/- cells.[12] 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 marrow tissues, leads to premature cellular senescence and therefore inhibition of haemopoietic function. Senescence, together with apoptosis, may constitute a major mechanism of haemopoietic cell depletion occurring in bone marrow failure.[citation needed]
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There are 22 genes responsible for FA,[20][21] one of them being the breast-cancer susceptibility geneBRCA2. They are involved in the recognition and repair of damaged DNA; genetic defects leave them unable to repair DNA. The FA core complex of 8 proteins is normally activated when DNA stops replicating because of damage. The core complex addsubiquitin, a small protein that combines withBRCA2 in another cluster to repair DNA (see FigureRecombinational repair of DNA double-strand damage). At the end of the process, ubiquitin is removed.[2]
Recent studies have shown that eight of these proteins, FANCA, -B, -C, -E, -F, -G, -L, and -M, assemble to form a core protein complex in the nucleus. According to current models, the complex moves from the cytoplasm into the nucleus following nuclear localization signals on FANCA and FANCE. Assembly is activated by replicative stress, particularlyDNA damage caused bycross-linking agents (such as mitomycin C or cisplatin) orreactive oxygen species (ROS) that is detected by the FANCM protein.[22]
Following assembly, the protein core complex activates FANCL protein, which acts as an E3 ubiquitin-ligase and monoubiquitinates FANCD2[23][24][25][26] and FANCI.[27][28]
Monoubiquitinated FANCD2, also known as FANCD2-L, then goes on to interact with aBRCA1/BRCA2 complex (see FigureRecombinational repair of DNA double-strand damage). Details are not known, but similar complexes are involved in genome surveillance and associated with a variety of proteins implicated in DNA repair and chromosomal stability.[29][30] With a crippling mutation in any FA protein in the complex, DNA repair is much less effective, as shown by its response to damage caused by cross-linking agents such ascisplatin,diepoxybutane[31] and Mitomycin C. Bone marrow is particularly sensitive to this defect.
In another pathway responding toionizing radiation, FANCD2 is thought to be phosphorylated by protein complex ATM/ATR activated by double-strand DNA breaks and takes part in S-phase checkpoint control. This pathway was proven by the presence of radioresistantDNA synthesis, the hallmark of a defect in theS phase checkpoint, in patients with FA-D1 or FA-D2. Such a defect readily leads to uncontrollable replication of cells and might also explain the increased frequency of AML in these patients.[citation needed]
FA proteins have cellular roles inautophagy andribosome biogenesis in addition to DNA repair.[21] FANCC, FANCA, FANCF, FANCL, FANCD2, BRCA1, and BRCA2 are required to clear damagedmitochondria from the cell (a process calledmitophagy).[32][33][34][35][36]BRCA1 (also known as FANCS) interacts with theribosomal DNA (rDNA)promoter and terminator in thenucleolus, the cellular location where ribosome biogenesis initiates, and is required fortranscription of rDNA.[37] FANCI functions in the production of thelarge ribosomal subunit by processingpre-ribosomal RNA (pre-rRNA), the transcription of pre-rRNA byRNAPI, maintaining levels of the mature28Sribosomal RNA (rRNA), and the global cellulartranslation of proteins byribosomes.[20] In the nucleolus, FANCI is predominantly in thedeubiquitinated form.[20] In addition, FANCA is required to maintain normal nucleolar morphology, for transcription of pre-rRNA, and global cellular translation.[38] FANCC, FANCD2, FANCG are also required to maintain normal nucleolar morphology and FANCG is also required for global cellular translation.[38] There may be a role for FA proteins outside the nucleolus in ribosome biogenesis or protein translation, as FANCI and FANCD2 were the only FA proteins associated withpolysomes.[38] Other inherited bone marrow failure syndromes also have defects in ribosome biogenesis or protein translation, includingdyskeratosis congenita,Diamond-Blackfan anemia, andShwachman Diamond Syndrome, and like these other diseases, FA may also be aribosomopathy.[20][21][39]
In humans, infertility is one of the characteristics of individuals with mutational defects in the FANC genes.[40] In mice,spermatogonia,preleptotenespermatocytes, and spermatocytes in the meiotic stages ofleptotene, zygotene and early pachytene are enriched for FANC proteins.[40] This finding suggests that recombinational repair processes mediated by the FANC proteins are active during germ cell development, particularly during meiosis, and that defects in this activity can lead toinfertility.[citation needed]
Microphthalmia andmicrocephaly are frequent congenital defects in FA patients. The loss ofFANCA andFANCG in mice causes neural progenitorapoptosis both during early developmentalneurogenesis and later during adult neurogenesis. This leads to depletion of the neuralstem cell pool with aging.[41] Much of the Fanconi anemia phenotype might be interpreted as a reflection of premature aging of stem cells.[41]
The first line of therapy isandrogens andhematopoietic growth factors, but only 50–75% of patients respond. A more permanent cure ishematopoietic stem cell transplantation.[42] If no potential donors exist, asavior sibling can be conceived bypreimplantation genetic diagnosis (PGD) to match the recipient'sHLA type.[43][44]
Many patients eventually developacute myelogenous leukemia (AML). Older patients are extremely likely to develop head and neck, esophageal, gastrointestinal, vulvar and anal cancers.[45] Patients who have had a successful stem cell 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.[citation needed]
The overarching medical challenge that Fanconi patients face is a failure of their bone marrow to produce blood cells. In addition, Fanconi patients are normally born with a variety of birth defects. A significant number of Fanconi patients have kidney problems, trouble with their eyes,developmental delay, and other serious defects, such asmicrocephaly (small head).[46]
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