HOME

TheInfoList



OR:

Fanconi anaemia (FA) is a rare
genetic disease A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosomal abnormality. Although polygenic disorders ...
resulting in impaired response to DNA damage. 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), and 90% develop
aplastic anemia Aplastic anemia is a cancer in which the body fails to make blood cells in sufficient numbers. Blood cells are produced in the bone marrow by stem cells that reside there. Aplastic anemia causes a deficiency of all blood cell types: red blood c ...
(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 The endocrine system is a messenger system comprising feedback loops of the hormones released by internal glands of an organism directly into the circulatory system, regulating distant target organs. In vertebrates, the hypothalamus is the neur ...
problem, with varying degrees of severity. FA is the result of a genetic defect in a cluster of proteins responsible for DNA repair via
homologous recombination Homologous recombination is a type of genetic recombination in which genetic information is exchanged between two similar or identical molecules of double-stranded or single-stranded nucleic acids (usually DNA as in cellular organisms but may be ...
. Treatment with androgens and hematopoietic (blood cell) growth factors can help bone marrow failure temporarily, but the long-term treatment is
bone marrow transplant Hematopoietic stem-cell transplantation (HSCT) is the transplantation of multipotent hematopoietic stem cells, usually derived from bone marrow, peripheral blood, or umbilical cord blood in order to replicate inside of a patient and to produ ...
if a donor is available. Because of the genetic defect in DNA repair, cells from people with FA are sensitive to drugs that treat cancer by DNA crosslinking, such as
mitomycin C Mitomycin C is a mitomycin that is used as a chemotherapeutic agent by virtue of its antitumour activity. Medical uses It is given intravenously to treat upper gastro-intestinal cancers (e.g. esophageal carcinoma), anal cancers, and breast c ...
. The typical age of death was 30 years in 2000. FA occurs in about one per 130,000 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 Guido Fanconi () (1 January 1892 – 10 October 1979) was a Swiss pediatrician. He was born in Poschiavo, a small village in the Canton of Grisons. Fanconi is regarded as one of the founders of modern pediatrics. He received his secondary sch ...
. It should not be confused with
Fanconi syndrome Fanconi syndrome or Fanconi's syndrome (, ) is a syndrome of inadequate reabsorption in the proximal renal tubules of the kidney. The syndrome can be caused by various underlying congenital or acquired diseases, by toxicity (for example, from tox ...
, a
kidney disorder Kidney disease, or renal disease, technically referred to as nephropathy, is damage to or disease of a kidney. Nephritis is an inflammatory kidney disease and has several types according to the location of the inflammation. Inflammation can b ...
also named after Fanconi.


Signs and symptoms

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 spot ''Café au lait'' spots, or ''café au lait'' macules, are flat, hyperpigmented birthmarks. The name ''café au lait'' is French for "coffee with milk" and refers to their light-brown color. Café au lait lesions with rough borders (" coast of Ma ...
s, 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.


Genetics

FA is primarily an
autosomal An autosome is any chromosome that is not a sex chromosome. The members of an autosome pair in a diploid cell have the same morphology, unlike those in allosomal (sex chromosome) pairs, which may have different structures. The DNA in autosomes ...
recessive genetic disorder. This means that two mutated
alleles An allele (, ; ; modern formation from Greek ἄλλος ''állos'', "other") is a variation of the same sequence of nucleotides at the same place on a long DNA molecule, as described in leading textbooks on genetics and evolution. ::"The chro ...
(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 The X chromosome is one of the two sex-determining chromosomes ( allosomes) in many organisms, including mammals (the other is the Y chromosome), and is found in both males and females. It is a part of the XY sex-determination system and XO sex ...
, a 50% chance exists that male offspring will present with Fanconi anemia. Scientists have identified 21 FA or FA-like genes: ''
FANCA Fanconi anaemia, complementation group A, also known as FAA, FACA and FANCA, is a protein which in humans is encoded by the ''FANCA'' gene. It belongs to the Fanconi anaemia complementation group (FANC) family of genes of which 12 complementation ...
'', ''
FANCB Fanconi anemia group B protein is a protein that in humans is encoded by the ''FANCB'' gene. Function The Fanconi anemia complementation group (FANC) currently includes FANCA, FANCB, FANCC, FANCD1 (also called BRCA2), FANCD2, FANCE, FANCF, FA ...
'', ''
FANCC Fanconi anemia group C protein is a protein that in humans is encoded by the ''FANCC'' gene. Structure Function The protein encoded by this gene delays the onset of apoptosis and promotes homologous recombination repair of damaged DNA. ...
'', ''
FANCD1 ''BRCA2'' and BRCA2 () are a human gene and its protein product, respectively. The official symbol (BRCA2, italic for the gene, nonitalic for the protein) and the official name (originally breast cancer 2; currently BRCA2, DNA repair associated) ...
(BRCA2)'', '' FANCD2'', ''
FANCE Fanconi anemia, complementation group E protein is a protein that in humans is encoded by the ''FANCE'' gene. The Fanconi anemia complementation group (FANC) currently includes FANCA, FANCB, FANCC, FANCD1 (also called BRCA2), FANCD2, FANCE, FANCF ...
'', ''
FANCF Fanconi anemia group F protein is a protein that in humans is encoded by the ''FANCF'' gene. Interactions FANCF has been shown to interact with Fanconi anemia, complementation group C, FANCG, FANCA and FANCE. Function FANCF is an adapto ...
'', ''
FANCG Fanconi anemia group G protein is a protein that in humans is encoded by the ''FANCG'' gene. Function FANCG, involved in Fanconi anemia, confers resistance to both hygromycin B and mitomycin C. FANCG contains a 5-prime GC-rich untranslated ...
'', ''
FANCI Fanconi anemia, complementation group I (FANCI) also known as KIAA1794, is a protein which in humans is encoded by the ''FANCI'' gene. Mutations in the ''FANCI'' gene are known to cause Fanconi anemia. Function The Fanconi anemia complementa ...
'', '' FANCJ (BRIP1)'', ''
FANCL E3 ubiquitin-protein ligase FANCL is an enzyme that in humans is encoded by the ''FANCL'' gene. Function The clinical phenotype of mutational defects in all Fanconi anemia (FA) complementation groups is similar. This phenotype is characteriz ...
'', ''
FANCM Fanconi anemia, complementation group M, also known as FANCM is a human gene. It is an emerging target in cancer therapy, in particular cancers with specific genetic deficiencies. Function The protein encoded by this gene, FANCM displays DNA b ...
'', '' FANCN (PALB2)'', ''FANCO (RAD51C),'' ''
FANCP SLX4 (also known as BTBD12 and FANCP) is a protein involved in DNA repair, where it has important roles in the final steps of homologous recombination. Mutations in the gene are associated with the disease Fanconi anemia. The version of SLX4 pre ...
(SLX4)'', '' FANCQ'' (''XPF), FANCS (BRCA1), FANCT (UBE2T), FANCU (XRCC2), FANCV (REV7),'' and ''FANCW (RFWD3)''. ''FANCB ''is the one exception to FA being
autosomal recessive In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and ...
, 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 Genetic testing, also known as DNA testing, is used to identify changes in DNA sequence or chromosome structure. Genetic testing can also include measuring the results of genetic changes, such as RNA analysis as an output of gene expression, or ...
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.


Pathogenesis

Clinically, hematological abnormalities are the most serious symptoms in 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 Macrocytosis is the enlargement of red blood cells with near-constant hemoglobin concentration, and is defined by a mean corpuscular volume (MCV) of greater than 100 femtolitres (the precise criterion varies between laboratories). The enlarged er ...
/
megaloblastic anemia Megaloblastic anemia is a type of macrocytic anemia. An anemia is a red blood cell defect that can lead to an undersupply of oxygen. Megaloblastic anemia results from inhibition of DNA synthesis during red blood cell production. When DNA synthes ...
, 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 Shwachman–Diamond syndrome (SDS), or Shwachman–Bodian–Diamond syndrome, is a rare congenital disorder characterized by exocrine pancreatic insufficiency, bone marrow dysfunction, skeletal abnormalities and short stature. After cystic fibro ...
, which primarily causes neutropenia. Most commonly, a low platelet count (
thrombocytopenia Thrombocytopenia is a condition characterized by abnormally low levels of platelets, also known as thrombocytes, in the blood. It is the most common coagulation disorder among intensive care patients and is seen in a fifth of medical patients and ...
) precedes a low neutrophil count (
neutropenia Neutropenia is an abnormally low concentration of neutrophils (a type of white blood cell) in the blood. Neutrophils make up the majority of circulating white blood cells and serve as the primary defense against infections by destroying bacteri ...
), with both appearing with relative equal frequencies. The deficiencies cause increased risk of
hemorrhage Bleeding, hemorrhage, haemorrhage or blood loss, is blood escaping from the circulatory system from damaged blood vessels. Bleeding can occur internally, or externally either through a natural opening such as the mouth, nose, ear, urethra, vagi ...
and recurrent infections, respectively. As FA is now known to affect DNA repair, specifically
homologous recombination Homologous recombination is a type of genetic recombination in which genetic information is exchanged between two similar or identical molecules of double-stranded or single-stranded nucleic acids (usually DNA as in cellular organisms but may be ...
, 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 A myelodysplastic syndrome (MDS) is one of a group of cancers in which immature blood cells in the bone marrow do not mature, and as a result, do not develop into healthy blood cells. Early on, no symptoms typically are seen. Later, symptoms may ...
, and
acute myeloid leukemia Acute myeloid leukemia (AML) is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal cells that build up in the bone marrow and blood and interfere with normal blood cell production. Symptoms may include ...
(AML).


Myelodysplastic syndromes

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 In cell biology, a precursor cell, also called a blast cell or simply blast, is a partially differentiated cell, usually referred to as a unipotent cell that has lost most of its stem cell properties. A precursor cell is also known as a proge ...
, is always less than 20%, with considerably more
dysplasia Dysplasia is any of various types of abnormal growth or development of cells (microscopic scale) or organs (macroscopic scale), and the abnormal histology or anatomical structure(s) resulting from such growth. Dysplasias on a mainly microscopic ...
, 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 Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes includ ...
or a failure of
programmed cell death Programmed cell death (PCD; sometimes referred to as cellular suicide) is the death of a cell (biology), cell as a result of events inside of a cell, such as apoptosis or autophagy. PCD is carried out in a biological process, which usually confers ...
. 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 or subsequent to the MDS. Furthermore, cells will show chromosomal aberrations, the most frequent being
monosomy Monosomy is a form of aneuploidy with the presence of only one chromosome from a pair. Partial monosomy occurs when a portion of one chromosome in a pair is missing. Human monosomy Human conditions due to monosomy: * Turner syndrome – People wit ...
7 and partial trisomies of chromosome 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 prompt
allogeneic Allotransplant (''allo-'' meaning "other" in Greek) is the transplantation of cells, tissues, or organs to a recipient from a genetically non-identical donor of the same species. The transplant is called an allograft, allogeneic transplant, o ...
hematopoietic progenitor cell transplant is an option).


Acute myeloid leukemia

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 Allotransplant (''allo-'' meaning "other" in Greek) is the transplantation of cells, tissues, or organs to a recipient from a genetically non-identical donor of the same species. The transplant is called an allograft, allogeneic transplant, o ...
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 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 Adenocarcinoma (; plural adenocarcinomas or adenocarcinomata ) (AC) is a type of cancerous tumor that can occur in several parts of the body. It is defined as neoplasia of epithelial tissue that has glandular origin, glandular characteristics, or b ...
. 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.


Molecular basis

There are 22 genes responsible for FA, one of them being the breast-cancer susceptibility gene
BRCA2 ''BRCA2'' and BRCA2 () are a human gene and its protein product, respectively. The official symbol (BRCA2, italic for the gene, nonitalic for the protein) and the official name (originally breast cancer 2; currently BRCA2, DNA repair associated) ...
. 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 ''BRCA2'' and BRCA2 () are a human gene and its protein product, respectively. The official symbol (BRCA2, italic for the gene, nonitalic for the protein) and the official name (originally breast cancer 2; currently BRCA2, DNA repair associated) ...
in another cluster to repair DNA (see Figure Recombinational repair of DNA double-strand damage). 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 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, particularly DNA damage caused by
cross-link In chemistry and biology a cross-link is a bond or a short sequence of bonds that links one polymer chain to another. These links may take the form of covalent bonds or ionic bonds and the polymers can be either synthetic polymers or natural ...
ing agents (such as mitomycin C or cisplatin) or reactive oxygen species (ROS) that is detected by the FANCM protein. 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 Breast cancer type 1 susceptibility protein is a protein that in humans is encoded by the ''BRCA1'' () gene. Orthologs are common in other vertebrate species, whereas invertebrate genomes may encode a more distantly related gene. ''BRCA1'' is a ...
/
BRCA2 ''BRCA2'' and BRCA2 () are a human gene and its protein product, respectively. The official symbol (BRCA2, italic for the gene, nonitalic for the protein) and the official name (originally breast cancer 2; currently BRCA2, DNA repair associated) ...
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 Cisplatin is a chemotherapy medication used to treat a number of cancers. These include testicular cancer, ovarian cancer, cervical cancer, breast cancer, bladder cancer, head and neck cancer, esophageal cancer, lung cancer, mesothelioma, brain ...
, 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 DNA synthesis is the natural or artificial creation of deoxyribonucleic acid (DNA) molecules. DNA is a macromolecule made up of nucleotide units, which are linked by covalent bonds and hydrogen bonds, in a repeating structure. DNA synthesis occurs ...
, 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 Autophagy (or autophagocytosis; from the Ancient Greek , , meaning "self-devouring" and , , meaning "hollow") is the natural, conserved degradation of the cell that removes unnecessary or dysfunctional components through a lysosome-dependent r ...
and ribosome biogenesis in addition to DNA repair. FANCC, FANCA, FANCF, FANCL, FANCD2, BRCA1, and BRCA2 are required to clear damaged mitochondria from the cell (a process called
mitophagy Mitophagy is the selective degradation of mitochondria by autophagy. It often occurs to defective mitochondria following damage or stress. The process of mitophagy was first described over a hundred years ago by Margaret Reed Lewis and Warren Harmo ...
).
BRCA1 Breast cancer type 1 susceptibility protein is a protein that in humans is encoded by the ''BRCA1'' () gene. Orthologs are common in other vertebrate species, whereas invertebrate genomes may encode a more distantly related gene. ''BRCA1'' is a ...
(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. In the nucleolus, FANCI is predominantly in the deubiquitinated form. In addition, FANCA is required to maintain normal nucleolar morphology, for transcription of pre-rRNA, and global cellular translation. FANCC, FANCD2, FANCG are also required to maintain normal nucleolar morphology and FANCG is also required for global cellular translation. 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 with polysomes. Other inherited bone marrow failure syndromes also have defects in ribosome biogenesis or protein translation, including dyskeratosis congenita, Diamond-Blackfan anemia, and Shwachman Diamond Syndrome, and like these other diseases, FA may also be a ribosomopathy.


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. 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 to infertility.


Neural stem cell homeostasis

Microphthalmia and
microcephaly Microcephaly (from New Latin ''microcephalia'', from Ancient Greek μικρός ''mikrós'' "small" and κεφαλή ''kephalé'' "head") is a medical condition involving a smaller-than-normal head. Microcephaly may be present at birth or it ...
are frequent congenital defects in FA patients. The loss of
FANCA Fanconi anaemia, complementation group A, also known as FAA, FACA and FANCA, is a protein which in humans is encoded by the ''FANCA'' gene. It belongs to the Fanconi anaemia complementation group (FANC) family of genes of which 12 complementation ...
and
FANCG Fanconi anemia group G protein is a protein that in humans is encoded by the ''FANCG'' gene. Function FANCG, involved in Fanconi anemia, confers resistance to both hygromycin B and mitomycin C. FANCG contains a 5-prime GC-rich untranslated ...
in mice causes neural progenitor
apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes includ ...
both during early developmental neurogenesis and later during adult neurogenesis. This leads to depletion of the neural
stem cell In multicellular organisms, stem cells are undifferentiated or partially differentiated cells that can differentiate into various types of cells and proliferate indefinitely to produce more of the same stem cell. They are the earliest type of ...
pool with aging. Much of the Fanconi anemia phenotype might be interpreted as a reflection of premature aging of stem cells.


Treatment

The first line of therapy is
androgens An androgen (from Greek ''andr-'', the stem of the word meaning "man") is any natural or synthetic steroid hormone that regulates the development and maintenance of male characteristics in vertebrates by binding to androgen receptors. This incl ...
and hematopoietic growth factors, but only 50–75% of patients respond. A more permanent cure is
hematopoietic stem cell transplantation Hematopoietic stem-cell transplantation (HSCT) is the transplantation of multipotent hematopoietic stem cells, usually derived from bone marrow, peripheral blood, or umbilical cord blood in order to replicate inside of a patient and to produ ...
. If no potential donors exist, a
savior sibling A savior baby or savior sibling is a child who is conceived in order to provide a stem cell transplant to a sibling that is affected with a fatal disease, such as cancer or Fanconi anemia, that can best be treated by hematopoietic stem cell transp ...
can be conceived by
preimplantation genetic diagnosis Preimplantation genetic diagnosis (PGD or PIGD) is the genetic profiling of embryos prior to implantation (as a form of embryo profiling), and sometimes even of oocytes prior to fertilization. PGD is considered in a similar fashion to prenatal ...
(PGD) to match the recipient's
HLA type The human leukocyte antigen (HLA) system or complex is a complex of genes on chromosome 6 in humans which encode cell-surface proteins responsible for the regulation of the immune system. The HLA system is also known as the human version of th ...
.


Prognosis

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 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. 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 Microcephaly (from New Latin ''microcephalia'', from Ancient Greek μικρός ''mikrós'' "small" and κεφαλή ''kephalé'' "head") is a medical condition involving a smaller-than-normal head. Microcephaly may be present at birth or it ...
(small head).Anemia, Fanconi


References


External links


Fanconi Anemia Research Fund

GeneReviews/NCBI/NIH/UW entry on Fanconi Anemia

OMIM entries on Fanconi Anemia
*
Fanconi's Anaemia
on patient.info {{DEFAULTSORT:Fanconi Anemia Chromosome instability syndromes Autosomal recessive disorders Aplastic anemias DNA replication and repair-deficiency disorders