Clinically, hematological abnormalities are the most serious symptoms of FA. By the age of 40, 98% of FA patients will have developed some type of
hematological abnormality. However, a few cases have occurred in which older patients have died without ever developing them. Symptoms appear progressively and often lead to complete
bone 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 developed
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 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 of
hemorrhage and recurrent
infections, respectively. As FA is now known to affect DNA repair, specifically
homologous recombination,
Acute myeloid leukemia 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. 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, although more recent published evidence suggests that earlier
allogeneic hematopoietic progenitor cell transplantation in children with FA is leading to better outcomes over time.
Bone marrow failure 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 haemopoietic
growth factors, these have been shown to promote leukemia, especially in patients with clonal cytogenetic abnormalities, and have severe side effects, including
hepatic adenomas and
adenocarcinomas. 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 developing
graft-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%. A recent report by Zhang et al. investigates the mechanism of bone marrow 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 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.
Molecular basis (ATM) is a
protein kinase that is recruited and activated by
DNA double-strand breaks. DNA double-strand damages also activate the
Fanconi anemia core complex (FANCA/B/C/E/F/G/L/M). The FA core complex
monoubiquitinates the downstream targets FANCD2 and FANCI. ATM activates (phosphorylates)
CHEK2 and FANCD2 CHEK2 phosphorylates BRCA1. Ubiquinated FANCD2 complexes with
BRCA1 and
RAD51. The PALB2 protein acts as a hub, bringing together BRCA1, BRCA2 and RAD51 at the site of a DNA double-strand break, and also binds to RAD51C, a member of the RAD51 paralog complex
RAD51B-
RAD51C-
RAD51D-
XRCC2 (BCDX2). The BCDX2 complex is responsible for RAD51 recruitment or stabilization at damage sites.
RAD51 plays a major role in
homologous recombinational repair of DNA during double-strand break repair. In this process, an ATP-dependent DNA strand exchange takes place in which a single strand invades base-paired strands of homologous DNA molecules. RAD51 is involved in the search for homology and strand pairing stages of the process.) There are 22 genes responsible for FA, one of them being the breast-cancer susceptibility gene
BRCA2. 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 adds
ubiquitin, a small protein that combines with
BRCA2 in another cluster to repair DNA (see Figure
Recombinational repair of DNA double-strand damage). At the end of the process, ubiquitin is removed. Following assembly, the protein core complex activates FANCL protein, which acts as an E3 ubiquitin-ligase and monoubiquitinates FANCD2 and FANCI. Monoubiquitinated FANCD2, also known as FANCD2-L, then goes on to interact with a
BRCA1/
BRCA2 complex (see Figure
Recombinational 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. 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 as
cisplatin,
diepoxybutane and Mitomycin C. Bone marrow is particularly sensitive to this defect. In another pathway responding to
ionizing 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 radioresistant
DNA synthesis, the hallmark of a defect in the
S 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. FA proteins have cellular roles in
autophagy and
ribosome biogenesis in addition to DNA repair.
BRCA1 (also known as FANCS) interacts with the
ribosomal DNA (rDNA)
promoter and terminator in the
nucleolus, the cellular location where ribosome biogenesis initiates, and is required for
transcription of rDNA. FANCI functions in the production of the
large ribosomal subunit by processing
pre-ribosomal RNA (pre-rRNA), the transcription of pre-rRNA by
RNAPI, maintaining levels of the mature
28S ribosomal RNA (rRNA), and the global cellular
translation of proteins by
ribosomes. FANCC, FANCD2, FANCG are also required to maintain normal nucleolar morphology and FANCG is also required for global cellular translation.
Spermatogenesis In humans, infertility is one of the characteristics of individuals with mutational defects in the FANC genes. In mice,
spermatogonia,
preleptotene spermatocytes, and spermatocytes in the meiotic stages of
leptotene, zygotene and early pachytene are enriched for FANC proteins. Much of the Fanconi anemia phenotype might be interpreted as a reflection of premature aging of stem cells. ==Treatment==