Анемия Фанкони: генетика, проявления и лечение редкого заболевания.

Fanconi anemia (FA) is a rare, autosomal recessive, genetic disease resulting in impaired response to DNA damage in the FA/BRCA pathway. Although it is a very rare disorder, study of this and other bone marrow failure syndromes has improved scientific understanding of the mechanisms of normal bone marrow function and development of cancer. Among those affected, the majority develop cancer, most often acute myelogenous leukemia (AML), MDS, and liver tumors. 90% develop aplastic anemia (the inability to produce blood cells) by age 40. About 60–75% have congenital defects, commonly short stature, abnormalities of the skin, arms, head, eyes, kidneys, and ears, and developmental disabilities. Around 75% have some form of endocrine problem, with varying degrees of severity. 60% of FA is FANC A, 16q24.3, which has later onset bone marrow failure. FA is the result of a genetic defect in a cluster of proteins responsible for DNA repair via homologous recombination. The well known cancer susceptibility genes BRCA1 and BRCA2 are also examples of FA genes (FANCS and FANCD1 respectively), and biallelic mutation of any of the two genes usually results in an embryonically 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 is bone marrow transplant if a donor is available. FA occurs in about one per 130,000 live births, with a higher frequency in Ashkenazi Jews and Afrikaners in South Africa. The disease is named after the Swiss pediatrician who originally described this disorder, Guido Fanconi. 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 with Fanconi syndrome, a kidney disorder also named after 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, including café 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. About 80% of FA will develop bone marrow failure by age 20. The first sign of a hematologic problem is usually petechiae and bruises, with later onset of pale appearance, feeling tired, and infections. Because macrocytosis usually precedes a low platelet count, patients with typical congenital anomalies associated with FA should be evaluated for an elevated red blood cell mean corpuscular volume.

FA is primarily an autosomal recessive genetic disorder. This means that two mutated alleles (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 one X chromosome, a 50% chance exists that male offspring will present with Fanconi anemia. 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), and FANCW (RFWD3). FANCB is the one exception to FA being autosomal recessive, as this gene is 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 who may be carriers of Fanconi anemia. Because of the failure of hematologic components—white blood cells, red blood cells, and platelets—to develop, the body's capabilities to fight infection, deliver oxygen, and form clots are all diminished.

FA patients are at elevated risk for the development of AML defined as 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 with the exception of 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 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.

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 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 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 increased 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, 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 occurred in bone marrow failure.

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 increase 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.

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. If no potential donors exist, a savior sibling can be conceived by preimplantation genetic diagnosis (PGD) to match the recipient's HLA type.

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 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. 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. A significant number of Fanconi patients have kidney problems, trouble with their eyes, developmental delay and other serious defects, such as microcephaly (small head).