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At least 19 recordsLinked to original sources
PubMed1997

Analysis of 65 Turkish patients with congenital aplastic anemia (Fanconi anemia and non-Fanconi anemia): Hacettepe experience.

During the last 14 years, 65 unrelated patients were diagnosed as having constitutional aplastic anemia (CAA). In 52 of 65 patients the diepoxybutane (DEB) test was positive. Comparison of several hematological and clinical parameters in Fanconi anemia (FA) (DEB+) and non-Fanconi anemia (non-FA)(DEB ) patients disclosed no statistically significant differences. The study indicated that in Turkey there were no peculiarities in associated congenital abnormalities in FA and non-FA. The rate of consanguinity was 78% in FA and 46% in non-FA, suggesting that also among the non-FA group recessively inherited disorders are hidden. The mean age at diagnosis in FA was 7.7+/-4.4 (1.8-12) and in non-FA 7.8+/-3.8 (2-15) years. Nine out of 52 FA and five out of 13 non-FA patients died during the follow-up period. Five of the 52 FA patients developed malignancies, three of them had acute myeloblastic leukemia (AML), one a squamous cell carcinoma of the gingiva, and another a hepatocellular carcinoma. Peliosis hepatica occurred in three of the FA and one of the non-FA patients. A total of seven patients stayed in remission without any medication. The remaining 58 patients were given 2-5 mg/kg of oxymetholone and 5 mg prednisolone treatment. Because of sustained remission, oxymetholone therapy was terminated in four of the 45 FA and two of the 13 non-FA patients. Detailed examination of the pedigrees of all of patients indicated the presence of multiple congenital anomalies. In seven of 52 FA and one of 13 non-FA patients there was increased risk for AML and/or other cancers among family members.

Abnormalities, Multiple↗
PubMed2000

Association of complementation group and mutation type with clinical outcome in fanconi anemia. European Fanconi Anemia Research Group.

Fanconi anemia (FA) is a clinically and genetically heterogeneous disorder. Clinical care is complicated by variable age at onset and severity of hematologic symptoms. Recent advances in the molecular biology of FA have allowed us to investigate the relationship between FA genotype and the nature and severity of the clinical phenotype. Two hundred forty-five patients from all 7 known complementation groups (FA-A to FA-G) were studied. Mutations were detected in one of the cloned FANC genes in 169 patients; in the remainder the complementation group was assigned by cell fusion or Western blotting. A range of qualitative and quantitative clinical parameters was compared for each complementation group and for different classes of mutation. Significant phenotypic differences were found. FA-G patients had more severe cytopenia and a higher incidence of leukemia. Somatic abnormalities were less prevalent in FA-C, but more common in the rare groups FA-D, FA-E, and FA-F. In FA-A, patients homozygous for null mutations had an earlier onset of anemia and a higher incidence of leukemia than those with mutations producing an altered protein. In FA-C, there was a later age of onset of aplastic anemia and fewer somatic abnormalities in patients with the 322delG mutation, but there were more somatic abnormalities in patients with IVS4 + 4A --> T. This study indicates that FA patients with mutations in the FANCG gene and patients homozygous for null mutations in FANCA are high-risk groups with a poor hematologic outcome and should be considered as candidates both for frequent monitoring and early therapeutic intervention. (Blood. 2000;96:4064-4070)

Abnormalities, Multiple↗
PubMed1983

Cytogenetic differentiation of Fanconi anemia, "idiopathic" aplastic anemia, and Fanconi anemia heterozygotes.

We have analyzed chromosome breaks in 8 patients with Fanconi anemia (FA), 42 with "idiopathic" aplastic anema (AA), 15 first-degree relatives of FA patients, and 13 controls. Their lymphocytes were treated in culture with three concentrations of mitomycin-C (MMC). A 60-fold increase in breaks was observed in FA patients as compared to AA patients, regardless of severity of clinical signs. The MMC-stress test was standardized to clearly differentiate FA from other pancytopenias in doubtful cases. Also, the effect of storage of MMC in solution was investigated. The data on SCEs of 12 subjects tested, 10 mo apart, showed an inverse relationship between length of storage of MMC and chromosome damage. The 10-month-old solution induced only one half as many SCEs as it induced at 4 months. Further, the usefulness and power of diepoxybutane (DEB) in detection of FA heterozygotes was investigated in 12 first-degree relatives of patients with Fanconi anemia and 12 healthy controls. The mean number of chromosome breaks per mitosis by DEB stress in obligate heterozygotes was 0.08 in comparison to 0.06 in controls. Four of twelve control subjects showed proportions of breaks almost identical to or higher than those of FA heterozygotes, ie, 0.12, 0.10, 0.10, and 0.11 breaks per mitosis. The responses of healthy controls to DEB could be separated into two groups: one with mean chromosome breaks of 0.11 per mitosis, and a second with mean breaks of 0.04 per mitosis. Thus, it appears that heterozygote detection by DEB stress of cultured lymphocytes is not unequivocal.

Adolescent↗
PubMed2003

A novel ubiquitin ligase is deficient in Fanconi anemia.

Fanconi anemia is a recessively inherited disease characterized by congenital defects, bone marrow failure and cancer susceptibility. Cells from individuals with Fanconi anemia are highly sensitive to DNA-crosslinking drugs, such as mitomycin C (MMC). Fanconi anemia proteins function in a DNA damage response pathway involving breast cancer susceptibility gene products, BRCA1 and BRCA2 (refs. 1,2). A key step in this pathway is monoubiquitination of FANCD2, resulting in the redistribution of FANCD2 to nuclear foci containing BRCA1 (ref. 3). The underlying mechanism is unclear because the five Fanconi anemia proteins known to be required for this ubiquitination have no recognizable ubiquitin ligase motifs. Here we report a new component of a Fanconi anemia protein complex, called PHF9, which possesses E3 ubiquitin ligase activity in vitro and is essential for FANCD2 monoubiquitination in vivo. Because PHF9 is defective in a cell line derived from an individual with Fanconi anemia, we conclude that PHF9 (also called FANCL) represents a novel Fanconi anemia complementation group (FA-L). Our data suggest that PHF9 has a crucial role in the Fanconi anemia pathway as the likely catalytic subunit required for monoubiquitination of FANCD2.

Amino Acid Sequence↗
PubMed2003

Genetic basis of Fanconi anemia.

Fanconi anemia is a rare autosomal recessive disease characterized by bone marrow failure, developmental anomalies, a high incidence of myelodysplasia and acute nonlymphocytic leukemia, and cellular hypersensitivity to cross linking agents. Five of the seven known Fanconi anemia proteins bind together in a complex and influence the function of a sixth, FANCD2, which colocalizes with BRCA1 in nuclear foci after genotoxic stress. Carboxy-terminal truncating mutations of the seventh Fanconi anemia gene, BRCA2, are hypomorphic and lead to FA-D1 and possibly FA-B. Because the Fanconi anemia alleles of BRCA2 fail to bind to Rad51 in response to genotoxic stress and Rad51 therefore fails to localize to nuclear damage foci, many investigators in the field suspect that the Fanconi anemia pathway supports the integrity of the Rad51 and BRCA1 and BRCA2 pathways as they function in homologous recombination repair. Because these abnormalities are common to all somatic cells, it is unlikely that dysfunction of this particular pathway results in tissue-specific apoptosis of hematopoietic cells. Indeed, at least one of the Fanconi anemia proteins, FANCC, exhibits functions in hematopoietic cells in addition to its role in the complex. Because FANCC protects hematopoietic cells from apoptotic cues in ways that do not require an intact heteromeric Fanconi anemia complex, it is reasonable to expect that the other Fanconi anemia gene products will have independent cytoplasmic and nuclear functions, particularly in hematopoietic and germ cells that seem to rely so substantially on an intact portfolio of Fanconi anemia proteins.

Fanconi Anemia↗
PubMed2003

Shared genetic susceptibility to breast cancer, brain tumors, and Fanconi anemia.

Fanconi anemia is an inherited disease characterized by bone marrow failure, congenital malformations, and predisposition to cancer. The breast cancer susceptibility gene BRCA2 was recently found to be associated with Fanconi anemia complementation group D1 (FA-D1). We examined four kindreds afflicted with Fanconi anemia for the presence of germline BRCA2 mutations. One kindred, of Ashkenazi Jewish ancestry, had five members who were diagnosed with breast cancer and two cousins who were BRCA2*6174delT/C3069X compound heterozygotes and had Fanconi anemia and brain tumors. In another kindred of Ashkenazi Jewish and Lithuanian Catholic ancestry, a child with Fanconi anemia and a medulloblastoma was a BRCA2*6174delT/886delGT compound heterozygote. Two other kindreds each contained a Fanconi anemia-afflicted child who developed medulloblastoma; one child was of Latin American ancestry and a compound heterozygote for BRCA2*I2490T/ 5301insA and the other was African American and a compound heterozygote for BRCA2*Q3066X/E1308X. Median age of the Fanconi anemia-afflicted children at brain tumor diagnosis was 3.5 years. The co-occurrence of brain tumors, Fanconi anemia, and breast cancer observed in one of these kindreds constitutes a new syndromic association. Individuals who carry a germline BRCA2 mutation and who plan to have children with a partner of Ashkenazi Jewish descent should consider undergoing genetic counseling.

Alleles↗
PubMed2003

Gene therapy for fanconi anemia.

Fanconi anemia is a hereditary syndrome of bone marrow failure, congenital anomalies, and a predisposition to malignancy. Most patients die from bone marrow failure. Cells from patients display a heightened sensitivity to DNA cross-linking agents with increased chromosomal breakage and increased cytotoxicity. Bone marrow from patients with Fanconi anemia have decreased numbers of hematopoietic progenitors when grown in culture. Transfer of the normal Fanconi anemia cDNA into cells from patients corrects the laboratory abnormalities, suggesting that gene transfer may prevent or reverse the bone marrow failure. Advances in gene transfer into human hematopoietic cells make this approach seem feasible. However, decreased numbers of stem cell targets may represent a significant obstacle. In addition, new insights on potential toxicities related to gene transfer have heightened a cautious approach. Fanconi anemia represents a prototype disorder for gene therapy and highlights the difficulties in adapting this technology to human disease.

Animals↗
PubMed1999

The molecular and cellular biology of Fanconi anemia.

Fanconi anemia is a rare autosomal recessive disease characterized by multiple congenital abnormalities, bone marrow failure, and cancer susceptibility. The mean age of onset of anemia is 8 years, and the mean survival is 16 years. Death usually results from complications of bone marrow failure. Considerable progress in Fanconi anemia research has resulted from the recent identification and cloning of three Fanconi anemia genes. The current review describes the structure and function of the Fanconi anemia genes and describes the role of the encoded Fanconi anemia proteins in a cellular pathway controlling chromosome stability.

Animals↗
PubMed2005

[Functions of FANCL in primordial germ cell formation and Fanconi anemia].

Fanconi anemia (FA) is a rare autosomal recessive disorder characterized clinically by congenital abnormalities, progressive bone marrow failure and cancer susceptibility. Cells from individuals with Fanconi anemia manifest features of spontaneous chromosomal instability and hypersensitivity to DNA cross-linking agents such as mitomycin C. Over 11 known Fanconi anemia gene products are involved in DNA damage response pathway. In the pathway, monoubiquitination of FANCD2 is a key step. A novel protein FANCL is a component of the nuclear FA complex, functioned as an ubiquitin E3 ligase and monoubiquitinylated FANCD2. FANCD2-Ub is targeted to chromatin, where it interacts with BRCA2 to repair DNA damage. In early embryo stage, FA pathway is probably involved in proliferation of PGCs. Mice deficient in FA proteins, such as FANCL, FANCC and FANCA, have a drastic reduction of primordial germ cells (PGC), resulting in male and female infertility in adult. In the adult male, FANCL and a few testis-specific proteins, GGN1 (gametogenetin protein 1), GGNBP1 (gametogenetin binding protein 1), GGNBP2 and OAZ3 (ornithine decarboxylase antizyme 3) form a novel testis-specific complex functioning in spermatogenesis. FANCL is involved in proliferation of PGCs in early embryo stage, and development of germ cells in adult.

Adult↗
PubMed1995

Bone marrow transplantation for Fanconi anemia.

Fanconi anemia is a genetic disorder associated with diverse congenital abnormalities, progressive bone marrow failure, and increased risk of leukemia and other cancers. Affected persons often die before 30 years of age. Bone marrow transplantation is an effective treatment, but there are few data regarding factors associated with transplant outcome. We analyzed outcomes of HLA-identical sibling (N = 151) or alternative related or unrelated donor (N = 48) bone marrow transplants for Fanconi anemia performed between 1978 and 1994 and reported to the International Bone Marrow Transplant Registry. Fanconi anemia was documented by cytogenetic studies in all cases. Patient, disease, and treatment factors associated with survival were determined using Cox proportional hazards regression. Two-year probabilities (95% confidence interval) of survival were 66% (58% to 73%) after HLA-identical siblings transplants and 29% (18% to 43%) after alternative donor transplants. Younger patient age (P .0001), higher pretransplant platelet counts (P = .04), use of antithymocyte globulin (P = .005), and use of low-dose (15 to 25 mg/kg) cyclophosphamide plus limited field irradiation (P = .009) for pretransplant conditioning and cyclosporine for graft-versus-host disease prophylaxis (P = .002) were associated with increased survival. Bone marrow transplants are effective therapy for Fanconi anemia. The adverse impact of increasing age and lower pretransplant platelet count on transplant outcome favors earlier intervention, especially when there is an HLA-identical sibling donor.

Adolescent↗
PubMed1995

Fanconi anemia.

Fanconi anemia is a phenotypically and genotypically heterogeneous syndrome in which patients manifest various congenital abnormalities, bone marrow failure, and predisposition to malignancy. The primary dermatologic manifestations are pigmentation abnormalities (hyperpigmentation, hypopigmentation, café-au-lait spots) and cutaneous malignancies. The gene for one of the complementation groups (FACC) has been cloned, and the gene product has been shown to have a cytoplasmic localization, ruling out a direct role for the Fanconi anemia gene in DNA repair. A better understanding of the function of the FACC polypeptide, and the cloning of genes for the other Fanconi anemia complementation groups, should lead to a better understanding of the basic problems of birth defects and cancer predisposition and the interaction of genetic and epigenetic factors in the pathogenesis of these problems.

Bone Marrow Diseases↗
PubMed1994

Evaluation of granulocyte-macrophage colony-stimulating factor for treatment of pancytopenia in children with fanconi anemia.

Fanconi anemia is a congenital syndrome characterized by multiple specific physical anomalies, progressive marrow failure, and a predisposition to acute leukemia. We studied the toxicity and efficacy of daily subcutaneous administration of recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients with Fanconi anemia and pancytopenia. The toxicity of GM-CSF at the doses and schedule used was minimal. Six of seven patients entered had an increase in the neutrophil count of 7- to 25-fold, which was maintained during the course of study. Despite increases in the reticulocyte count, increases in hemoglobin concentration were rare. No improvement in platelet count was evident in any patient. No patient has evidence of leukemia after up to 19 months of continuous GM-CSF exposure, and all five surviving patients remain responsive to treatment. Although the optimal dose, schedule, and choice of cytokine for patients with marrow failure and Fanconi anemia are not established by this preliminary study, the data indicate that (1) GM-CSF may be able to palliate at least the neutropenia and potentially the neutropenic complications of the disease, (2) this effect can be sustained for more than 1 year, and (3) rapid evolution of acute leukemia is unlikely to be a frequent outcome of such treatment. The clinical impact of GM-CSF or other cytokines in patients with Fanconi anemia and pancytopenia remains to be established by further studies.

Adolescent↗
PubMed2004

Medulloblastoma as a first presentation of fanconi anemia.

Fanconi anemia is a chromosomal instability syndrome associated with certain congenital abnormalities, defective hemopoiesis, and an increased risk of developing acute myeloid leukemia and some solid tumors. The diagnosis can be made at birth if congenital abnormalities are present but is often made in childhood when hematologic complications develop. The authors report a case of Fanconi anemia diagnosed in a child with no congenital abnormalities and normal bone marrow who first presented with a cerebellar medulloblastoma. The authors discuss diagnostic and therapeutic implications for such malignancies in Fanconi anemia.

Bone Neoplasms↗
PubMed2002

Molecular pathogenesis of fanconi anemia.

Fanconi anemia (FA) is a rare autosomal recessive chromosomal breakage disorder characterized by the childhood onset of aplastic anemia, developmental defects, cancer susceptibility, and cellular hypersensitivity to DNA-cross-linking agents. FA patients can be divided into at least 8 complementation groups (FA-A, FA-B, FA-C, FA-D1, FA-D2, FA-E, FA-F, and FA-G). FA proteins encoded by 6 cloned FA genes (FANCA, FANCC, FANCD2, FANCE, FANCF, and FANCG) cooperate in a common pathway, culminating in the monoubiquitination of FANCD2 protein and colocalization of FANCD2 and BRCA1 proteins in nuclear foci. These BRCA1 foci have been implicated in the process of homologous recombination-mediated DNA repair. In this review, we will summarize the current progress in the field of FA research and highlight some of the potential functions of the FA pathway in DNA-damage response.

Animals↗
PubMed1992

Nuclease modification in Chinese hamster cells hypersensitive to DNA cross-linking agents--a model for Fanconi anemia.

Fanconi anemia is a human inherited disease that is characterized by cellular hypersensitivity to DNA cross-linking agents. A number of potential experimental models for that disorder have been developed by selecting mutants that are hypersensitive to bifunctional mutagens. The six mutants of that class in Drosophila, all of which map to the mus308 locus, express an alteration in a mitochondrial nuclease. A recent extension of that observation to cell lines from complementation group A of Fanconi anemia has established a new cellular phenotype for that disorder. In the current study an analogous enzyme has been analyzed in eight recently isolated Chinese hamster cell lines that are hypersensitive to cross-linking agents. Among these lines. V-H4 and V-B7 are shown to exhibit an enzyme modification analogous to that observed in the mutant Drosophila and human cells. These results validate the nuclease assay as an indicator of the Fanconi defect and further establish the V-H4 cell line as a valuable cellular model for analysis of the Fanconi A defect.

Animals↗
PubMed2000

[Fanconi anemia].

Fanconi anemia is a rare autosomal recessive disorder which is characterized with chromosomal fragility and hypersensitivity to DNA cross-link agents. There are large variability in phenotype even among patients of single family. Therefore, diagnosis depends solely on hypersensitivity to DNA cross-link agents. At present at least 8 complement groups are known and 3 genes, FANCA, FANCC and FANCG, have been cloned. There is controversies concerning intracellular localization and interaction between these genes. Although the mechanism of the final effect of products of these genes leading to Fanconi anemia phenotype, chromosomal fragility and ultimately development of cancers is not fully understand, increasing evidence shows that gene products seems to work to prevent oxygen injury by reactive oxygen species rather than repair of DNA injury.

Chromosome Fragility↗
PubMed1997

Molecular biology of Fanconi anemia.

Fanconi anemia (FA) is a rare, autosomal recessive disease characterized by multiple congenital abnormalities, bone marrow failure, and cancer susceptibility. Although traditionally described as a classic clinical syndrome, as more is discovered regarding its basic molecular and cell biology, FA is emerging as a true premalignant syndrome. Two of the genes of the five known complementation groups have been cloned, and work to understand their function is underway. Further understanding of these gene products has lent new ideas concerning modes of novel therapy, including gene therapy. The impact of molecular biology on our understanding of basic biology and the clinical care of FA patients is discussed.

Cell Cycle Proteins↗