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CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From the Division of Medical and Molecular Genetics,
GKT School of Medicine, Guy's Hospital, London, UK; Department of
Hematology, Bone Marrow Transplant Unit, Hôpital Saint-Louis,
Paris, France; Department of Hematology, Hammersmith Hospital, London,
UK; Virchow-Klinikum, Berlin, Germany; Ospedale Elena d'Aosta, Naples,
Italy; Hacettepe University, Ankara, Turkey; Baragwanath Hospital,
Bertsham, South Africa; Departments of Human Genetics and Paediatrics,
University of the Orange Free State Medical School, Bloemfontein, South
Africa; Department of Human Genetics, Free University of Amsterdam, The
Netherlands; Department of Pediatrics, Leiden University Medical
Centre, The Netherlands; Genetics Service, IRCCS Ospedale CSS, San
Giovanni Rotondo, Italy; Department of Human Genetics, University of
the Witwatersrand, Johannesburg, South Africa.
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 Fanconi anemia (FA) is an autosomal recessive
disorder characterized clinically by progressive pancytopenia, diverse
congenital abnormalities, and predisposition to malignancy,
particularly acute myelogenous leukemia (AML).1 FA
patients exhibit extreme clinical heterogeneity and may have
abnormalities in any major organ system.2 Common physical
findings include abnormal skin pigmentation, growth retardation, radial
ray or other skeletal malformations, microphthalmia, and renal or
urinary tract malformations. Less common clinical features are genital,
gastrointestinal or cardiac malformations, hearing loss, mental
retardation, and central nervous system
abnormalities.1,3,4 Aplastic anemia (AA) develops at an
average age of 7 years, but a considerable range has been
reported.5 Some FA patients have a relatively mild phenotype, with normal skeletal development, subclinical hematopoietic abnormalities, and survival into the third or fourth
decade.6,7 Other patients have a more severe phenotype,
with skeletal abnormalities, early onset AA, and
cancer.8-10 Hematopoietic stem cell transplantation (SCT)
offers the only current possibility of a cure for the hematologic complications.11
Cells cultured from FA patients exhibit increased spontaneous
chromosomal aberrations and hypersensitivity to DNA cross-linking agents such as mitomycin C (MMC) and diepoxybutane
(DEB).12 This is used as a diagnostic criterion for FA
because of the difficulty of making the diagnosis on the basis of
clinical manifestations alone. FA is also a genetically heterogeneous
disorder, with 8 different complementation groups (A-H) having been
described,13-14 which has subsequently been revised to
7.15 This heterogeneity has largely been verified by
molecular cloning of FANCA on chromosome 16q24.3,16,17 FANCC on 9q22.3,13
FANCF on 11p13-p15,18 and FANCG on
9p13.19 The prevalence of the different complementation groups has been shown to vary considerably according to ethnic origin.20,21 FA-A is the most prevalent group, accounting
for 65% of all cases.22
One possible explanation for the wide variety of clinical expression
could be differences in complementation group, because the
respective genes could function either at different points in the same
pathway or in different pathways that lead to similar but not identical
clinical conditions. Alternatively, variations in severity could result
from different mutations within the same gene23 and other
genetic or environmental factors.24-27 Early studies of
FA-C patients showed that a clinical severity score was lower in
patients with the 322delG mutation in FANCC than in patients
with IVS4 + 4A The European Fanconi Anemia Research Group (EUFAR)30 has
collected clinical, molecular, and cellular data on 245 FA patients from 24 countries, representing all 7 confirmed complementation groups.
These data have been analyzed to determine whether specific complementation groups, mutations, or classes of mutation in FA genes
are associated with differences in clinical outcome such as age of
onset of aplastic anemia, survival, the incidence of leukemia, or the
presence of somatic abnormalities. This paper presents the results of
the study, which identified several highly significant associations
among specific groups of patients and aspects of their clinical
phenotype that may be relevant to the clinical management of the FA patient.
Patients
Hematology and malignancies
Somatic abnormalities The prevalence of each specific somatic abnormality was compared in the different groups. The extent of the malformations was also assessed according to the number of anatomic sites involved, as previously described,31 excluding skin abnormalities and growth retardation for this purpose. The following were each considered as anatomic sites: (1) the head, including eyes (small eyes, strabismus, epicanthal folds, hypertelorism), ears (deafness, abnormal shape, atresia, dysplasia, low set, canal stenosis, abnormal middle ear), face (microcephaly, micrognathia, triangular face), and neck (short, sprengel); (2) the skeleton (including thumb and radial abnormalities); (3) the kidneys, (4) the gastrointestinal tract; (5) the urogenital tract, including small testes and cryptorchidism; (6) the cardiovascular system; and (7) the central nervous system (CNS). The CNS abnormalities included hydrocephaly, encephalocele, and spina bifida.Molecular and cell biology Complementation analysis. Fusion of lymphoblastoid cell lines to genetically marked reference cell lines from known FA complementation groups was carried out as previously described.14 Western blotting. This was carried out in selected cell lines using anti-FANCA, anti-FANCF, and anti-FANCG antibodies, as previously described.32 Mutation screening. RNA was extracted from cell lines and genomic DNA from peripheral blood samples in 4 different laboratories and screened by SSCP analysis, heteroduplex analysis, chemical cleavage, or sequencing. Most of the mutations detected have been reported in previous publications16,17,19,33-37 or have been submitted to the International FA Mutation database [http://www.rockefeller.edu/fanconi/mutate]. Null mutations were classified as those that would be predicted to produce no FA protein (frameshifts, stop codons, and large deletions), and "altered protein" mutations as missense mutations and in-frame deletions. Also included in the latter group were frameshifts in the most distal 10% of the coding sequence of the genes, because C-terminal truncating mutations may be associated with functional protein.38 In 29 cases (11.8%), the predicted effect of the mutation was verified by Western blotting. Statistical analysis The proportion of patients with a specific abnormality was compared in the complementation groups with global and pairwise tests for differences, using the 2 test or Fisher exact test
for small numbers. The numbers of abnormalities and numbers of anatomic
sites were compared across groups using the t test and
analysis of variance. The predictive value of specific abnormalities
for a patient's complementation group was assessed using logistic
regression. Survival analysis was used to compare the age at onset of
hematologic abnormalities, the age at diagnosis of AML or MDS, and
survival after diagnosis by complementation group. Kaplan-Meier
estimates were calculated and differences among the complementation
groups were tested using the nonparametric log-rank test. Estimates of
survival after diagnosis will contain a bias toward longer-surviving
patients because patients diagnosed shortly before the start of the
study who also died before the start of the study would not be
included. Analyses of malformations and survival were performed by: (1)
comparing the common mutations in complementation groups A and C with
other patients within the complementation group and with all other FA
patients; (2) comparing patients with 2 null mutations against patients
with mutations causing an altered protein; and (3) comparing patients
with 2 mutations at the 5' end of the gene with those with 2 mutations at the 3' end. Possible bias in the analysis of somatic abnormalities as a result of familial clustering was assessed by repeating the analysis with only the first diagnosed sibling in each family. Because
of the complexity of the cross tabulation of the sites of somatic
abnormalities and complementation group and to the relatively small
sample size, no attempt was made to control study-wide error.
Significant associations should therefore be confirmed in a future
study, and nonsignificant associations that involved small numbers of
observations should be viewed as inconclusive. All statistical testing
used Splus5 (MathSoft Inc, Seattle, WA).
Complementation group and mutations Complementation group was assigned in 245 FA patients by cell fusion, by the detection of at least one clearly pathogenic mutant allele,39 by the absence of detectable FANCA, FANCF, or FANCG protein on a Western blot, or by the existence of a sibling classified by one or more of these methods. The number of patients assigned by each of these methods is listed in Table 1. This also shows that 101 patients were assigned by 2 or more independent methods, and all of these results were concordant. This led to the classification of 172 patients as group A (70.2%), one as group B (0.4%), 34 as group C (13.9%), 3 as group D (1%), 5 as group E (2%), 6 as group F (2.5%), and 24 as group G (9.8%). The spectrum of mutations observed in the 169 patients with at least one mutation was highly heterogeneous, and the majority of patients from a nonconsanguineous mating were compound heterozygotes. Sixty-eight different pathogenic mutations were found in FANCA, 11 in FANCC, 11 in FANCG, and 5 in FANCF, 75.6% of which were predicted to generate null alleles and 24.3% to produce an altered protein. There were 159 patients in whom both mutations were identified, of which 105 were homozygous for null mutations (66.0%). The proportion of homozygous nulls in the 3 main complementation groups was not significantly different, with 75 of 114 in FA-A (65.8%), 22 of 34 in FA-C (64.7%), and 8 of 11 in FA-G (72.7%). Apparent founder mutations were noted in the Irish population (FANCA/deletion of exons 11-14 in 7 patients), in Ashkenazi Jews (FANCC/IVS4 + 4A T in 5 patients), and in South
African Afrikaners (FANCA/deletion of exons 12-31 in 44 patients, deletion of exons 11-17 in 10 patients, 3398delA in 7 patients). Two other common mutations were found without any obvious
founder effect (FANCA/1263delF in 9 patients and
FANCC/322delG in 17 patients).
Phenotypes in the complete patient cohort Most patients had an abnormal blood count at presentation (93%), and the mean age at onset of hematologic abnormalities was 7.6 years. At the time of analysis, 72% of the patients were still living. The mean age at last observation was 14 years, including patients who died (14.4 years in FA-A, 16.2 years in FA-C, and 11.5 years in FA-G). The mean age at death for those patients who had died was 13.9 years. SCT had been carried out in 21% of patients, and 61% required transfusions. In the course of their disease, 9% of patients had AML develop, 8% MDS, and 6% nonhematologic malignancies. The pattern of somatic abnormalities in the full cohort of patients is listed in Table 2.
Phenotypes in different complementation groups Pairwise comparisons were carried out among groups A, C, and G because comparison against the total cohort would be dominated by FA-A, and these 3 groups were represented by a substantial number of patients. Hematology and malignancies.
No significant difference among FA-A, FA-C, and FA-G was found for age
at diagnosis of FA (P = .41), age at onset of hematologic abnormalities (P = .076, Figure
1A), requirement for transfusions (P = .24), and solid tumors (P = .46). The
mean number of parameters indicative of severe cytopenia (as defined in
"Patients, materials, and methods") were 1.56 in FA-A, 0.89 in
FA-C, and 2.11 in FA-G. Analysis of variance showed a significant
effect of complementation group (P = .035), and pairwise
analysis showed that FA-G was more severe than FA-C (Wilcoxon rank-sum
test, P = .016). Survival to age 10 years after diagnosis
was 62% for FA-A, 73% for FA-C, and 50% for FA-G (Figure 1B), but
postdiagnosis survival was not statistically significantly different
either globally for groups A, C, and G (P = 0.69) or for
pairwise analyses (P > .25). Postdiagnosis survival
analysis for all complementation groups will be biased against patients
with very short survival who died before the start of the study
(described in "Patients, materials, and methods"). There were
significant differences by complementation group in rates of AML
(P = .001), MDS (P = .04), and AML or MDS
(P = .0003), with FA-G having a higher rate of AML or MDS
than FA-A and FA-C (Figure 1C). The proportion of cases with AML/MDS
was 23 of 172 (13.4%) in FA-A, 7 of 34 (20.6%) in FA-C, and 8 of 24 (33.3%) in FA-G. Estimates from the survival analysis of the
proportion of FA patients who had AML/MDS develop by age 10 years were
less than 1% for FA-A (n = 158), 0% for FA-C (n = 25), and 33%
for FA-G (n = 18). In the rare complementation groups, it is worth noting that the 3 FA-D patients presented with either very mild or no
hematologic abnormalities at a mean age of 13.3 years, but the
difference from all FA patients was not statistically significant.
Somatic abnormalities. Three-way tests for differences in specific somatic abnormalities and in the total number of abnormalities across groups A, C, and G were carried out. If these were significant (P < .05), pairwise tests were then performed. The results are presented in Table 2. Themean number of somatic abnormalities was significantly higher in FA-A than in FA-C, and in FA-G compared with FA-C, but FA-A and FA-G were similar. When considering specific somatic abnormalities, FA-C had significantly less growth retardation, fewer head abnormalities and radial ray defects than FA-A or FA-G, and fewer skin abnormalities and urogenital malformations than FA-A. More central nervous system defects were found in FA-C than FA-A, but these were all associated with a particular mutation (see below). Analysis of the number of anatomic sites, which excludes the mild and common abnormalities of skin and growth retardation,31 also showed a less severe phenotype in FA-C compared with FA-A or FA-G. These analyses were repeated by excluding any siblings of the index case to assess the possible effects of familial clustering. The results of the 3-way tests were very similar to those with all siblings, which suggests that differences across the groups are not related to familial clustering. Logistic regression analysis did not reveal differences in somatic abnormalities that were sufficiently marked to permit accurate prediction of the major complementation groups. Although sample numbers were small for the rare complementation groups FA-D, FA-E, and FA-F, they showed a higher rate of involvement of anatomic sites. Significant results were obtained when each of these 3 groups was compared with the overall sample (P = .003 for FA-D, P < 10 7 for FA-E,
P = .024 for FA-F). Furthermore, 3 of 5 FA-E patients presented with central nervous system malformations, and this number is
significantly different when compared with the overall sample
(P < .001).
Common mutations Pairwise analyses were carried out for each of 7 common mutations in FANCA or FANCC against the remaining patients in the corresponding complementation group, and against all FA patients. Patients were scored as positive for a specific mutation if they had at least one copy of it.Hematology and malignancies.
No significant differences were found for any of the common mutations
in FANCA with regard to age of diagnosis, age of onset of
hematologic symptoms, or the proportion of patients with severe cytopenia. A higher rate of AML or MDS was found in patients with at
least one delE12-31 mutation (n = 44) compared with patients with
other mutations in FANCA (P = .004). Survival
analysis showed that by age 20 years an estimated 55.3% of patients
with at least one delE12-31 mutation had AML or MDS develop, compared
with 13.3% in other patients from FA-A. In patients who were
homozygous for delG322 (n = 12), there was a later age of onset of
hematologic symptoms compared with all FA patients
(P = .036), with an estimated 33.3% of these patients
developing symptoms by age 10 compared with 78.5% of all FA. It was
not possible to analyze the hematologic course and survival in patients
with the FANCC IVS4 + 4A Somatic abnormalities.
The prevalence of somatic abnormalities in patients with the common
mutations was compared with rates in patients with other mutations in
the same complementation group. Significant differences are shown in
Table 3. Patients with at least one
delE12-31 mutation in FANCA or with the FANCC
mutation IVS4 + 4A
Class of mutation Hematology and malignancies. Patients with 2 FANCA mutations leading to a null allele had an earlier age of onset of hematologic abnormalities (7.2 years vs 10.3 years, P = .006, Figure 1D), and a shorter survival after diagnosis (P = .056, Figure 1E). Their survival 10 years postdiagnosis was 55.8% compared with 83% for patients with an altered FANCA protein. They also had a higher proportion of AML/MDS (P = .018, Figure 1F), when compared with patients with an altered protein. Significance levels were similar when patients with 2 null mutations were compared with patients with 2 mutations leading to an altered protein. There was no significant difference in the incidence of solid tumors in FANCA null homozygotes compared to those with at least one altered protein allele, but the number of malignancies observed was small (n = 6). No significant difference was found for any of the parameters for patients with mutations at the 5' end of FANCA compared to those with 3' mutations. The number of patients with different classes of mutations in FANCC and FANCG (n = 11) was too small for comparison. Somatic abnormalities. No significant difference was found in the pattern or the proportion of somatic abnormalities or anatomic sites when FA-A patients with 2 mutations leading to a null allele were compared with FA-A patients with at least one mutation leading to an altered protein, or for FA-A patients with 5' mutations versus 3' mutations. However, a lower rate of somatic abnormalities (P = .005) and anatomic sites (P = .006) was found in FA-C patients with 2 null mutations compared with those with at least one mutation leading to an altered protein.
The diagnosis and treatment of Fanconi anemia is complicated by the great variability in the severity of the disease, particularly the wide range in the age of onset of hematologic abnormalities and survival. Monitoring the progression of the disease and knowing when to introduce major therapeutic interventions, such as SCT, presents a significant challenge. Previous work from our group showed that the extent of severe somatic abnormalities was a strong predictor of survival after matched, unrelated SCT.31 In the current study, we have investigated the possibility of defining risk groups in FA by examining the relationship between genotype and phenotype, first by separating patients by complementation group or type of mutation, and then comparing the clinical phenotypes of these subgroups. Examination of the hematologic profiles of the most prevalent complementation groups (A, C, and G) did not reveal significant differences in age of onset of aplastic anemia, but cytopenia was more severe in FA-G, and AML or MDS occurred much earlier and in a higher proportion of patients in this group. There was no significant difference in the incidence of solid tumors in these groups, but numbers were small. Survival after diagnosis was lowest in FA-G, but this result was not statistically significant. This may reflect the lack of a genuine difference or insufficient power to detect a moderate effect. The overall finding was of a more severe hematologic course in FA-G, with the least severe course in FA-C. The extent of significant somatic abnormalities was similar in FA-A and FA-G, but very much lower in FA-C patients, particularly for abnormalities of the head and radial ray. There was also evidence of a higher rate of somatic abnormalities in the rare complementation groups, but this observation will need to be followed up in larger samples as more of these patients are identified. Investigation of the clinical phenotypes associated with specific
mutations in FA is complicated by great heterogeneity in the mutational
spectrum of the known FA genes; thus numbers of patients with a
specific mutation are generally small, and the majority are compound
heterozygotes. However, within FA-A we found that the presence of at
least one allele with a delE12-31 mutation was associated with a higher
rate of AML or MDS and a high rate of severe somatic abnormalities. In
FA-C, the 322delG mutation was associated with milder hematologic
symptoms when compared with all FA patients, and there was a lower rate
of somatic abnormalities, with 16 of 17 patients having normal thumbs
and absence of deep organ malformations. This result is broadly similar
to those from previous genotype-phenotype correlation studies in
FA-C.23,28,29 In contrast, the IVS4 + 4A We also searched for a significant difference between mutations predicted to lead to the absence of an FA protein and those predicted to lead to an altered protein. In some cases, these predictions would not be fulfilled, as demonstrated by the detection of a FANCC protein with an amino terminal truncation in the 322delG mutation.29 However, when we compared FA-A patients with 2 null alleles with FA-A patients with at least one allele leading to an altered protein, we found striking differences in the hematologic phenotype. Complete loss of FANCA protein was associated with a severe phenotype, whereas patients with an altered protein had a milder phenotype with a later age at onset of aplastic anemia, longer survival after diagnosis, and a lower prevalence of AML or MDS. Because the spectrum of FANCA null mutations was heterogeneous, the effect is not driven by a single severe mutation. Thus, the class of mutation present in any individual patient presents an additional variable that may override the influence of the complementation group. The phenotypic variations that we have observed among different complementation groups and different classes of mutation raises the question of whether they can be explained in terms of what is known about the biology of the FA proteins. The FANCG protein interacts with FANCA, and this complex is reduced or disrupted in several other complementation groups.32,41-43 It has been suggested that the FA proteins are involved in the fidelity of repair of double-stranded breaks in DNA.44 If the FANCG protein is a key molecule in a multiprotein complex, then the lack of this protein may result in the disruption of the complex and affect the function of multiple FA proteins. This might lead to a higher degree of chromosomal breakage than in the other groups, and thus a more severe hematologic profile and a higher incidence of leukemia. The milder clinical phenotype observed in FA-A patients with an altered FANCA protein would not be unexpected if these proteins had partial activity. The mutant protein FANCA-H1110P, for example, fails to correct MMC sensitivity in a cell survival assay,45 but does form a complex with FANCG.32 It may therefore enable some part of FANCG function to occur. The milder 322delG mutation produces a frameshift in exon 1 and would therefore not be expected to produce any FANCC protein. However, cell lines with this mutation are reported to produce a 50 kD protein by reinitiation at met55, which confers partial correction of MMC sensitivity when overexpressed in FA-C cells.29 A protective effect for this protein in vivo is not yet established, because patients with this mutation are reported to exhibit a high frequency of DEB-induced chromosomal breakage.23 We believe that the results of this study have important implications
for the clinical management of the FA patient. FA-G patients and those
with 2 null mutations in the FANCA gene appear to constitute
high-risk groups, with a more severe hematologic course and a high
incidence of AML or MDS. Conversely, most FA-C patients in our study,
with the exception of those with the IVS4 + 4A
We thank the families with Fanconi anemia and Ralf Dietrich (Deutsche Fanconi Anemia Hilfe e.V) for their cooperation.
A complete list of the members of the European Fanconi Anemia Research Group is given at the end of this article.
Submitted February 18, 2000; accepted August 14 2000.
Supported by the European Union BIOMED program and the Fanconi Anemia Research Fund (US). L.F. is the recipient of a grant from l'Association pour la Récherche contre le Cancer.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Christopher G. Mathew, Division of Medical and Molecular Genetics, 8th floor Guy's Tower, Guy's Hospital, SE1 9RT London, UK; email: christopher.mathew{at}kcl.ac.uk.
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European Fanconi Anemia Research Group (EUFAR) (in alphabetical order): Drs S. E. Ball, R. Calzone, J. Cavenagh, F. Desai, De Wolf, G. R. Evans, Giuang Ji, C. Gutteridge, A. V. Hoffbrand, Hyde, P. Jacobs, C. Jameson, C. Karabus, M. Karwacki, H. Kayserili, J. C. Llerena, S. P. Mohan, A. O'Marcaigh, J. C. Opperman, Phillips, I. Roberts, P. Roux, E. Samochatova, H. Schmitt, D. Schuler, C. E. M. De Die-Smulders, S. Temtamy, C. Tautz, A. Vora, Williams, and C. Zeilder.
© 2000 by The American Society of Hematology.
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P. S. Rosenberg, B. P. Alter, and W. Ebell Cancer risks in Fanconi anemia: findings from the German Fanconi Anemia Registry Haematologica, April 1, 2008; 93(4): 511 - 517. [Abstract] [Full Text] [PDF]
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F. Locatelli, M. Zecca, A. Pession, G. Morreale, D. Longoni, P. Di Bartolomeo, F. Porta, F. Fagioli, B. Nobili, M. E. Bernardo, et al. The outcome of children with Fanconi anemia given hematopoietic stem cell transplantation and the influence of fludarabine in the conditioning regimen: a report from the Italian pediatric group Haematologica, October 1, 2007; 92(10): 1381 - 1388. [Abstract] [Full Text] [PDF]
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C Shaw-Smith Oesophageal atresia, tracheo-oesophageal fistula, and the VACTERL association: review of genetics and epidemiology J. Med. Genet., July 1, 2006; 43(7): 545 - 554. [Abstract] [Full Text] [PDF]
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J. Soulier, T. Leblanc, J. Larghero, H. Dastot, A. Shimamura, P. Guardiola, H. Esperou, C. Ferry, C. Jubert, J.-P. Feugeas, et al. Detection of somatic mosaicism and classification of Fanconi anemia patients by analysis of the FA/BRCA pathway Blood, February 1, 2005; 105(3): 1329 - 1336. [Abstract] [Full Text] [PDF]
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 F. J. Couch, M. R. Johnson, K. Rabe, L. Boardman, R. McWilliams, M. de Andrade, and G. Petersen Germ Line Fanconi Anemia Complementation Group C Mutations and Pancreatic Cancer Cancer Res., January 15, 2005; 65(2): 383 - 386. [Abstract] [Full Text] [PDF]
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P. S. Rosenberg, Y. Huang, and B. P. Alter Individualized risks of first adverse events in patients with Fanconi anemia Blood, July 15, 2004; 104(2): 350 - 355. [Abstract] [Full Text] [PDF]
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B. Hirsch, A. Shimamura, L. Moreau, S. Baldinger, M. Hag-alshiekh, B. Bostrom, S. Sencer, and A. D. D'Andrea Association of biallelic BRCA2/FANCD1 mutations with spontaneous chromosomal instability and solid tumors of childhood Blood, April 1, 2004; 103(7): 2554 - 2559. [Abstract] [Full Text] [PDF]
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A. Shimamura and A. D. D'Andrea Subtyping of Fanconi anemia patients: implications for clinical management Blood, November 1, 2003; 102(9): 3459 - 3459. [Full Text] [PDF]
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M D Tischkowitz and S V Hodgson Fanconi anaemia J. Med. Genet., January 1, 2003; 40(1): 1 - 10. [Abstract] [Full Text]
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A. Shimamura, R. M. de Oca, J. L. Svenson, N. Haining, L. A. Moreau, D. G. Nathan, and A. D. D'Andrea A novel diagnostic screen for defects in the Fanconi anemia pathway Blood, December 15, 2002; 100(13): 4649 - 4654. [Abstract] [Full Text] [PDF]
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A. D. D'Andrea, N. Dahl, E. C. Guinan, and A. Shimamura Marrow Failure Hematology, January 1, 2002; 2002(1): 58 - 72. [Abstract] [Full Text]
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Y. Yang, Y. Kuang, R. M. De Oca, T. Hays, L. Moreau, N. Lu, B. Seed, and A. D. D'Andrea Targeted disruption of the murine Fanconi anemia gene, Fancg/Xrcc9 Blood, December 1, 2001; 98(12): 3435 - 3440. [Abstract] [Full Text] [PDF]
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M. Grompe and A. D'Andrea Fanconi anemia and DNA repair Hum. Mol. Genet., October 1, 2001; 10(20): 2253 - 2259. [Abstract] [Full Text] [PDF]
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A. L. Medhurst, P. A.J. Huber, Q. Waisfisz, J. P. de Winter, and C. G. Mathew Direct interactions of the five known Fanconi anaemia proteins suggest a common functional pathway Hum. Mol. Genet., February 1, 2001; 10(4): 423 - 429. [Abstract] [Full Text] [PDF]
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Top
Abstract
Introduction
10 g/dL, white blood count (WBC)
