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A case of Fanconi anemia with terminal acute leukemia is reported. Clones with chromosome abnormalities were observed in bone marrow cells. The patterns of marker chromosome distribution in these clones suggests the occurrence of a somatic segregation mechanism.
Fanconi Anemia (FA) is a heritable syndrome characterized by DNA damage repair deficits, frequent malformations and a significantly elevated risk of bone marrow failure, leukemia, and mucosal head and neck squamous cell carcinomas (HNSCC). Hematopoietic stem cell gene therapy can prevent marrow failure and lower leukemia risk, but mucosal gene therapy to lower HNSCC risk remains untested. Major knowledge gaps include an incomplete understanding of how rapidly gene-corrected cellular lineages could spread through the oral epithelium, and which delivery parameters are critical for ensuring efficient gene correction. To answer these questions, we extended an agent-based model of the oral epithelium to include the delivery of gene correction in situ to FA cells and determine the competitive dynamics between cellular lineages with and without gene correction. We found that only gene-corrected lineages with substantial proliferative advantages (probability of resisting displacement out of the basal layer [Formula: see text]) could spread on clinically relevant timelines, and that these lineages were initially at high risk of loss in the generations following correction. Delivering gene correction to many cells minimizes the risk of loss, while delivery to many distinct locations within a tissue maximizes the rate of spread. To determine the impact of mucosal gene therapy in preventing the clonal expansion of pre-cancerous mutations, we compared the expected burden of TP53 mutations in simulated tissue sections with and without gene correction. We found that when FA cells have elevated genome instability or a TP53-dependent proliferative advantage, gene correction can substantially reduce the accumulation of pro-tumorigenic mutations. This model illustrates the power of computational frameworks to identify critical determinants of therapeutic success to enable experimental optimization and support novel and effective gene therapy applications.
Fanconi Anemia (FA) is a heritable syndrome characterized by DNA damage repair deficits, frequent malformations and a significantly elevated risk of bone marrow failure, leukemia, and mucosal head and neck squamous cell carcinomas (HNSCC). Hematopoietic stem cell gene therapy can prevent marrow failure and lower leukemia risk, but mucosal gene therapy to lower HNSCC risk remains untested. Major knowledge gaps include an incomplete understanding of how rapidly gene-corrected cellular lineages could spread through the oral epithelium, and which delivery parameters are critical for ensuring efficient gene correction. To answer these questions, we extended an agent-based model of the oral epithelium to include the delivery of gene correction in situ to FA cells and the competitive dynamics between cellular lineages with and without gene correction. We found that only gene-corrected lineages with substantial proliferative advantages (probability of resisting displacement out of the basal layer ≥ 0.1) could spread on clinically relevant timelines, and that these lineages were initially at high risk of loss in the generations following correction. Delivering gene correction to many cells minimizes the risk of loss, while delivery to many distinct locations within a tissue maximizes the rate of spread. To determine the impact of mucosal gene therapy in preventing the clonal expansion of pre-cancerous mutations, we compared the expected burden of TP53 mutations in simulated tissue sections with and without gene correction. We found that when FA cells have elevated genome instability or a TP53-dependent proliferative advantage, gene correction can substantially reduce the accumulation of pro-tumorigenic mutations. This model illustrates the power of computational frameworks to identify critical determinants of therapeutic success to enable experimental optimization and support novel and effective gene therapy applications.
Fanconi Anemia (FA) is the most frequent inherited bone marrow failure syndrome. A role for the XRCC2 gene in FA was suspected in 2012 and confirmed in 2016, but only two affected individuals have been described thus far, and no long-term follow-up is available. Here we present two young related adults born to consanguineous parents, in whom we identified the homozygous p.(Arg215Ter) variant in XRCC2. Both patients presented with mild intellectual disability, microcephaly, distinctive facial features, short stature, thumb abnormalities, and abnormal skin pigmentation. Unlike in FA, DEB test resulted negative in peripheral blood during childhood and no cytopenia, clonal evolution, or other hematological complications were detected until the age of 19 and 20 years, respectively. Our report suggests that the homozygous p.(Arg215Ter) variant in XRRC2 causes a distinctive FA-like disorder, characterized by the typical physical characteristics seen in FA, but a lack of major hematological manifestations in childhood, and the presence of a more pronounced neurodevelopmental phenotype than that seen in FA.
A 6-year-old boy with Fanconi anemia, developed acute myelomonocytic leukemia with marker chromosomes from an interchange in the malignant clone in the bone marrow. The possible aetiological role of therapy, the morphological characteristics and chromosome aberrations of the bone marrow cell line are discussed in relation to previous reported cases of Fanconi anemia in which acute leukemia has supervened.
We are treating successfully for seven years a nineteenyear-old girl with Fanconi's aplastic anemia combining androgenes and corticosteroids. The cytogenetic analyses of the other family members showed typical chromosome abnormalities in her father, mother and a twelve-year old sister. In the bone marrow of this sister there are already present the first morphological abnormalities, although the values of her peripheral blood counts are still normal. In the present paper we are discussing when to start the specific therapy in the affected sister.
Previous studies of the expression of SV40 genetic information by skin fibroblasts included limited numbers of cell donors and failed to adequately consider possible effects of age, sex, and ethnic origin on assay results. A population of 76 healthy subjects were selected for study following determination of personal and family disease history and karyological analysis. Skin fibroblasts from these individuals were tested for expression of SV40 T-antigen by indirect immunofluorescent assay. The data were normally distributed and showed no significant differences between the age, sex, or ethnic groups tested. The occurrence of rare karyological anomalies in this control population had no effect on T-antigen expression. Fibroblasts from 10 Fanconi anemia patients demonstrated significantly elevated expression of T antigen compared to the well-defined control population, based on simple statistical criteria. T-antigen expression was elevated in two young patients prior to the onset of anemia and did not appear to correlate with the incidence or severity of other specific symptoms. Thus, elevated T-antigen expression in Fanconi anemia fibroblasts reflects an actual defect at the cellular level, rather than clinical, age, sex or ethnic factors not previously considered.
Measurements of plating efficiency, accumulation of metaphases and generation times have shown that fibroblast from patients with Fanconi anemia (FA) have decreased probability of completing a further division after successful mitosis. Thus FA cells show decreased growth rates and increased generation times. We have also measured the survival of FA fibroblasts and lymphoblasts after treatment with a variety of mutagens. All FA cells show an increased sensitivity to drugs such as MMC and psoralen plus long wave length UV which cause DNA interstrand crosslinks. FA strains show varying degrees of sensitivity to these drugs and the extent of this sensitivity seems to be characteristic of each patient. FA cells are equal to controls in their sensitivity to other alkylating agents such as ethyl methane sulfonate, N-methyl-N1-nitro-N-nitrosoguanidine and actinomycin D. Both the decreased growth and increased drug sensitivity may result from defect in DNA replication or repair.
We have studied the pattern of chromosome instability in cultured fibroblasts and fetal membrane cells from a fetus aborted by an individual with a history of a previous child affected with Fanconi anemia (FA). These cells exhibited a low level of spontaneous chromosome instability. Upon treatment with diepoxybutane (DEB), chromosome breakage increased to a level comparable to that reported earlier in DEB-treated FA heterozygous cells. Cultured cells derived from chromosomally normal fetuses which served as controls did not show DEB-induced chromosome breakage. This observation suggests that the fetus studied is heterozygous for the FA gene. The ability to distinguish readily between the three genotypes (homozygous FA, heterozygous FA, and normal) in an in vitro stress system that measures the response of the cells to a clastogenic agent makes available a test for the prenatal and postnatal detection of the FA gene.
A 15 year old boy with the Fanconi malformation-aplastic anemia syndrome developed erythroleukemia and died of multiple arterial thromboses and hemorrhage. He was one of 10 siblings including 3 affected sisters. He was short of stature and had hypoplastic thumbs; his testes were small and secondary sexual characteristics were inadequately developed. At autopsy he was found to have very few spermatogonia, i.e., a histological picture compatible with the "Sertoli-cell-only" defect. Male hypogonadism in other chromosome breakage syndromes (the Bloom syndrome and ataxia telangiectasia) may have a similar pathogenesis.
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Results of the investigation of 3 children aged from 2 to 7,5 with diagnosed aplastic anemia of Fanconi type are presented. Two children were females and one child was a male. Their illness symptoms appeared at the age of one, three and four respectively. All three patients had similar symptomes: palenes, tiredness, epistaxis, appearance of hemorrhagic syndrome and delayed growth. The following anomalies were also present: small size, microcephaly, mandibular hypoplasia, high palate and malformation of the urinary tract. In one child ductus Botalli persistens was also revealed. The laboratory findings showed presence of pancytopenia of the blood and increased level of both iron and erythropoietin in the serum. The karytype of two children revealed several cells with broken chromatin and with polyploid and tetraploid cells. The meiogram showed presence of all cells in bone marrow but in lowered number. Celularity I.
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Four patients with Fanconi's anemia were evaluated with 99mTc-sulfur colloid bone marrow scans. The scans revealed similar paradoxical and irregular tracer distribution in all four patients. Normal to increased activity was demonstrated in the proximal metaphyses of the humeri with varying degrees of increased activity in more primitive marrow sites in the distal diaphyses of the humeri and tibia, the distal metaphyses of the humeri and femora, and the proximal metaphyses of the ulnae, radii, and tibia. Skip areas of normal distribution were seen in the proximal diaphyses of the humeri and femora. Although the scan reflects only the reticuloendothelial portion of bone marrow, it may be of some value in the differential diagnosis of pancytopenia.
Two cases of Fanconi anemia in brothers are described. Reticulocytosis and shortened survival of red blood cells in younger brother were observed. Ethiopathogenesis, therapy and prognosis are discussed.