Fanconi anemia ( FA ) is a rare genetic disease that results in impaired response to DNA damage. Although a very rare disorder, studies of bone marrow and other bone marrow syndrome have increased scientific understanding of the mechanisms of normal bone marrow function and cancer progression. Among those affected, the majority developed cancer, most often acute myelogenous leukemia, and 90% developed bone marrow failure (inability to produce blood cells) by age 40. Approximately 60-75% of people had congenital defects, general short stature, abnormalities skin, arms, head, eyes, kidneys, and ears, and developmental defects. About 75% of people have some form of endocrine problem, with varying degrees of severity.
FA is the result of a genetic defect in a group of proteins responsible for DNA repair through homologous recombination.
Treatment with androgens and hematopoietic growth factors (blood cells) may help temporary bone marrow failure, but long-term treatment is bone marrow transplantation if donors are available. Because of genetic defects in DNA repair, cells from people with FA are sensitive to drugs that treat cancer with crosslinked DNA, such as mitomycin C. The typical death age is 30 years in 2000.
FA occurs at about one per 130,000 births, with higher frequencies in Ashkenazi Jews in Israel and Afrikaner in South Africa. The disease is named after a Swiss pediatrician who originally described this disorder, Guido Fanconi. Should not be confused with Fanconi syndrome, kidney disorders are also named Fanconi.
Video Fanconi anemia
Signs and symptoms
FA is characterized by bone marrow failure, AML, solid tumors, and developmental abnormalities. Classic features include abnormal thumbs, fingers that do not exist, short stature, skin hyperpigmentation, including ling spot cafes, abnormal facial features (triangular face, microcephaly), abnormal kidney, and decreased fertility. Many FA patients (about 30%) do not have any of the classic physical findings, but fragile Diepoxybutane chromosomes show an increase in chromosomal damage can make a diagnosis. About 80% of the FA will develop bone marrow failure by age 20.
The first sign of a haematological problem is usually petechiae and bruises, with pale appearance, fatigue, and infection. Since macrocytosis usually precedes low platelet counts, patients with typical congenital anomalies associated with the FA should be evaluated for an increase in mean red blood cell volume.
Maps Fanconi anemia
Genetics
FA is primarily an autosomal recessive genetic disorder. This means that two mutated alleles (one from each parent) are needed to cause the disease. The risk is 25% that each subsequent child will have an FA. Approximately 2% of cases of FA are recessive X-linked, meaning that if the mother carries an Fanconi anemia allele mutates on one X chromosome, it is likely 50% there that male offspring will present with Fanconi anemia.
Scientists have identified 17 FA or FA-like gene: FANCA, FANCB, FANCC, FANCD1 (BRCA2), FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ (BRIP1), FANCL, FANCM, FANCN (PALB2) FANCP (SLX4), FANCS (BRCA1), RAD51C and XPF . FANCB is the only exception for an autosomal recessive FA, because it is present on the X chromosome. These genes are involved in DNA repair.
The carrier frequency in the Ashkenazi Jewish population is about one in 90. Genetic counseling and genetic testing are recommended for families that may be carriers of Fanconi anemia.
Because of the hematological component failure to thrive - white blood cells, red blood cells, and platelets - the body's ability to fight infections, deliver oxygen, and form clumps all diminish.
Pathogenesis
Clinically, hematologic abnormalities are the most serious symptoms in the FA. At age 40, 98% of FA patients will develop several types of hematologic abnormalities. However, some cases have occurred where older patients have died without ever developing it. Symptoms appear progressively, and often lead to total bone marrow failure. While at birth, the amount of blood normally is normal, macrocytosis/megaloblastic anemia, defined as the enormous red blood cells, is the first detectable disorder, often within the first decade of life (average age of onset is 7 years). In the next 10 years, more than 50% of patients with haematological disorders develop pancytopenia, defined as abnormalities in two or more blood cell lineages. This is in contrast to Diamond-Blackfan anemia, which affects only erythrocytes, and Shwachman-Diamond syndrome, which mainly causes neutropenia. Most commonly, low platelet count (thrombocytopenia) precedes low neutrophil count (neutropenia), with both appearing with relatively equal frequency. Lacking causes an increased risk of recurrent bleeding and infection, respectively.
Because the FA is now known to affect DNA repair, particularly homologous recombination, and given current knowledge of dynamic cell division in bone marrow, finding patients more likely to develop bone marrow failure, myelodysplastic syndrome, and acute myeloid leukemia (AML) is not surprising.
Myelodysplastic Syndrome
MDSs, formerly known as preleukemia, are a group of bone marrow neoplastic diseases that share many of the features of AML morphology, with some important differences. First, the percentage of undifferentiated progenitor cells, blast cells, is always less than 20%, with much more dysplasia, defined as cytoplasmic and nuclear morphological changes in erythroid precursors, granulocytic, and megakaryocytic, than what is usually seen in AML cases. These changes reflect delayed apoptosis or failure of programmed cell death. When not treated, MDS can cause AML in about 30% of cases. Due to the nature of the pathology of the FA, the diagnosis of MDS can not be done only through cyto- cetic analysis of the spinal cord. Indeed, only when morphological analysis of the marrow cells is performed, that the diagnosis of MDS can be ascertained. Upon examination, FA patients affected by MDS will show many clonal variations, appearing either before or after MDS. Furthermore, the cells will show chromosomal aberrations, most commonly being monosomy 7 and partial trisomy of chromosome 3q 15. Monitoring of monosomy 7 in marrow correlates well with an increased risk of developing AML and with a very poor prognosis, death generally occurs within 2 years (except cell transplantation allogenic hematopoietic progenitor is an option).
Acute myeloid leukemia
FA patients have a high risk for the development of AML defined as the presence of 20% or more of myeloid explosions in the bone marrow or 5 to 20% of myeloid explosions in the blood. All AML subtypes can occur in the FA with the promyelocytic exception. However, myelomonocytic and acute monocytic are the most commonly observed subtypes. Many MDS patient diseases evolve into AML if they persist long enough. In addition, the risk of developing AML increases with bone marrow failure.
Although the risk of developing MDS or AML before age 20 was only 27%, this risk increased to 43% at age 30 and 52% at age 40. Historically, even with marrow transplants, about a quarter of FA patients diagnosed with MDS/ALS have died from associated causes of MDS/ALS within two years, although recent published evidence suggests that previous allogeneic hematopoietic progenitor cell transplants in child- children with FA lead to better outcomes over time.
Bone marrow failure
The last major haematological complication associated with FA is bone marrow failure, which is defined as inadequate blood cell production. Several types of failure are observed in FA patients, and generally precede MDS and AML. Detection of a decrease in blood count is generally the first sign used to assess treatment needs and possible transplantation. While most FA patients are initially responsive to androgen therapy and haemopoietic growth factors, it has been shown to increase leukemia, especially in patients with clonal cytogenetic disorders, and has severe side effects, including liver adenoma and adenocarcinoma. The only treatment left is bone marrow transplantation; However, such operations have a relatively low success rate in FA patients when unrelated donors (30% survive 5 years). Therefore, it is important to transplant from brothers who are HLA-identical. In addition, due to increased susceptibility of FA patients to chromosomal damage, pre-transplant conditioning can not include high-dose radiation or immunosuppressant, thus increasing the likelihood of patients developing graft-versus-host disease. If all precautions are taken, and marrow transplants are performed within the first decade of life, the probability of survival two years can reach 89%. However, if the transplant was performed at an age older than 10 years, the two-year survival rate fell to 54%.
A recent report by Zhang et al. investigated the mechanism of bone marrow failure in FANCC -/- cells. They hypothesize and successfully demonstrate that repeated cycles of hypoxia-reoxygenation, as seen by haemopoietic and progenitor cells when they migrate between hyperoxic blood and the hypoxic marrow tissue, cause premature cell aging and therefore inhibit haemopoietic function. Senescence, along with apoptosis, may be a major mechanism of haemopoietic cell depletion that occurs in bone marrow failure.
Molecular basis
There are 19 genes responsible for FA, one of which is the BRCA2 breast cancer susceptibility genes. They are involved in the introduction and repair of damaged DNA; genetic defects make them unable to repair DNA. The FA's core complex of 8 proteins is usually activated when the DNA stops replicating due to damage. The core complex adds ubiquitin, a small protein that joins BRCA2 in another cluster to repair the DNA (see Figure Repair of double strand DNA recombination ). At the end of the process, ubiquitin is removed.
Recent studies have shown that eight of these proteins, FANCA, -B, -C, -E, -F, -G, -L and -M assemble to form the core protein complex in the nucleus. According to the current model, the complex moves from the cytoplasm to the nucleus following a nuclear localization signal at FANCA and FANCE. The assembly is activated by replicative stress, especially DNA damage caused by crosslinking agents (such as mitomycin C or cisplatin) or reactive oxygen species (ROS) detected by FANCM proteins.
After assembly, the protein core complex activates the FANCL protein that acts as E3 ubiquitin-ligase and monoubquitinates FANCD2.
Monoubiquitinated FANCD2, also known as FANCD2-L, then proceeds to interact with the BRCA1/BRCA2 complex (see Figure Repair double-stranded DNA recombination ). Details are unknown, but similar complexes are involved in genome surveillance and are associated with various proteins involved in DNA repair and chromosome stability. With crippling mutations in any FA protein in the complex, DNA repair is much less effective, as indicated by its response to damage caused by crosslinking agents such as cisplatin, diepoxybutane and Mitomycin C. Bone marrow is highly sensitive to this defect.
In another pathway that responds to ionizing radiation, FANCD2 is considered phosphorylated by an ATM/ATR protein complex that is activated by double-stranded DNA breakage, and takes part in the postal S-phase control. This pathway is evidenced by the synthesis of radioresistant DNA, characteristic of defects in the S phase checkpoint, in patients with FA-D1 or FA-D2. Such defects easily lead to uncontrolled cell replication and may also explain the increased frequency of AML in these patients.
Spermatogenesis
In humans, infertility is one of the characteristics of individuals with mutated defects in the FANC gene. In mice, spermatogonia, preleptoten spermatocytes, and spermatocytes in the leptotene meiotic stage, zygotene and early pachytene were enriched for FANC protein. These findings suggest that the recombination process mediated by FANC proteins is active during the development of germ cells, especially during meiosis, and that defects in these activities can cause infertility.
Nerve stem cell Homeostasis
Microphthalmia and microcephaly are common congenital defects in FA patients. The loss of FANCA and FANCG in rats causes neural progenitor apoptosis both during the development of early neurogenesis and later during adult neurogenesis. This causes the depletion of nerve stem cell pools with aging. Many phenotypes of Fanconi anemia may be interpreted as a reflection of premature aging of stem cells.
Treatment
First-line therapy is androgen and hematopoietic growth factor, but only 50-75% of patients respond. A more permanent cure is a hematopoietic stem cell transplant. If there are no potential donors, rescue relatives may be conceived by preimplantation genetic diagnosis (PGD) to match the recipient HLA type.
Prognosis
Many patients end up developing acute myelogenous leukemia (AML). Older patients are very likely to develop head and neck, esophageal, gastrointestinal, vulvar and anus cancers. Patients who have successfully performed bone marrow transplants and, thus, recovered from blood problems associated with the FA still have to undergo regular checkups to look for signs of cancer. Many patients do not reach adulthood.
The overall medical challenge facing Fanconi patients is their bone marrow failure to produce blood cells. In addition, Fanconi patients are usually born with various birth defects. A large number of Fanconi patients have kidney problems, problems with their eyes, developmental backwardness and other serious defects, such as microcephaly (small head).
See also
- The fingers are missing
- BRCA2
- PALB2
- Family RecQ
References
External links
- Fanconi Anemia Research Fund
- GeneReviews/NCBI/NIH/UW entered in Fanconi Anemia
- OMIM entry in Fanconi Anemia
- Fanconi anemia in Curlie (based on DMOZ)
- Hope Charitable Trust Fanconi - based in the UK, with Eu and International Link
- Fanconi Anemia FAmily Support - based in the UK
- Fanconi's anemia in patient.info
Source of the article : Wikipedia
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