scholarly journals Diagnostic Overlap between Fanconi Anemia and the Cohesinopathies: Roberts Syndrome and Warsaw Breakage Syndrome

Anemia ◽  
2010 ◽  
Vol 2010 ◽  
pp. 1-7 ◽  
Author(s):  
Petra van der Lelij ◽  
Anneke B. Oostra ◽  
Martin A. Rooimans ◽  
Hans Joenje ◽  
Johan P. de Winter
Keyword(s):  
Fanconi Anemia ◽  
Bone Marrow Failure ◽  
Clinical Manifestations ◽  
Nijmegen Breakage Syndrome ◽  
Inherited Disease ◽  
Chromosomal Breakage ◽  
Metaphase Chromosomes ◽  
Roberts Syndrome ◽  
Premature Centromere Division ◽  
Multiple Symptoms

Fanconi anemia (FA) is a recessively inherited disease characterized by multiple symptoms including growth retardation, skeletal abnormalities, and bone marrow failure. The FA diagnosis is complicated due to the fact that the clinical manifestations are both diverse and variable. A chromosomal breakage test using a DNA cross-linking agent, in which cells from an FA patient typically exhibit an extraordinarily sensitive response, has been considered the gold standard for the ultimate diagnosis of FA. In the majority of FA patients the test results are unambiguous, although in some cases the presence of hematopoietic mosaicism may complicate interpretation of the data. However, some diagnostic overlap with other syndromes has previously been noted in cases with Nijmegen breakage syndrome. Here we present results showing that misdiagnosis may also occur with patients suffering from two of the three currently known cohesinopathies, that is, Roberts syndrome (RBS) and Warsaw breakage syndrome (WABS). This complication may be avoided by scoring metaphase chromosomes—in addition to chromosomal breakage—for spontaneously occurring premature centromere division, which is characteristic for RBS and WABS, but not for FA.

scholarly journals Diagnosis of Fanconi Anemia: Mutation Analysis by Multiplex Ligation-Dependent Probe Amplification and PCR-Based Sanger Sequencing

Anemia ◽  
2012 ◽  
Vol 2012 ◽  
pp. 1-13 ◽  
Author(s):  
Johan J. P. Gille ◽  
Karijn Floor ◽  
Lianne Kerkhoven ◽  
Najim Ameziane ◽  
Hans Joenje ◽  
...  
Keyword(s):  
Fanconi Anemia ◽  
Sanger Sequencing ◽  
Bone Marrow Failure ◽  
Genetic Diagnosis ◽  
Cost Effective ◽  
Inherited Disease ◽  
Dna Testing ◽  
Founder Mutations ◽  
Chromosomal Breakage ◽  
Developmental Defects

Fanconi anemia (FA) is a rare inherited disease characterized by developmental defects, short stature, bone marrow failure, and a high risk of malignancies. FA is heterogeneous: 15 genetic subtypes have been distinguished so far. A clinical diagnosis of FA needs to be confirmed by testing cells for sensitivity to cross-linking agents in a chromosomal breakage test. As a second step, DNA testing can be employed to elucidate the genetic subtype of the patient and to identify the familial mutations. This knowledge allows preimplantation genetic diagnosis (PGD) and enables prenatal DNA testing in future pregnancies. Although simultaneous testing of all FA genes by next generation sequencing will be possible in the near future, this technique will not be available immediately for all laboratories. In addition, in populations with strong founder mutations, a limited test using Sanger sequencing and MLPA will be a cost-effective alternative. We describe a strategy and optimized conditions for the screening ofFANCA, FANCB, FANCC, FANCE, FANCF,andFANCGand present the results obtained in a cohort of 54 patients referred to our diagnostic service since 2008. In addition, the follow up with respect to genetic counseling and carrier screening in the families is discussed.

scholarly journals Diagnosis of Fanconi Anemia: Mutation Analysis by Next-Generation Sequencing

Anemia ◽  
2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Najim Ameziane ◽  
Daoud Sie ◽  
Stefan Dentro ◽  
Yavuz Ariyurek ◽  
Lianne Kerkhoven ◽  
...  
Keyword(s):  
Fanconi Anemia ◽  
Clinical Symptoms ◽  
Massively Parallel Sequencing ◽  
Bone Marrow Failure ◽  
Genetic Diagnosis ◽  
Chromosomal Breakage ◽  
Developmental Defects ◽  
Pathogenic Mutations ◽  
High Cancer Risk ◽  
Generation Sequencing

Fanconi anemia (FA) is a rare genetic instability syndrome characterized by developmental defects, bone marrow failure, and a high cancer risk. Fifteen genetic subtypes have been distinguished. The majority of patients (≈85%) belong to the subtypes A (≈60%), C (≈15%) or G (≈10%), while a minority (≈15%) is distributed over the remaining 12 subtypes. All subtypes seem to fit within the “classical” FA phenotype, except for D1 and N patients, who have more severe clinical symptoms. Since FA patients need special clinical management, the diagnosis should be firmly established, to exclude conditions with overlapping phenotypes. A valid FA diagnosis requires the detection of pathogenic mutations in a FA gene and/or a positive result from a chromosomal breakage test. Identification of the pathogenic mutations is also important for adequate genetic counselling and to facilitate prenatal or preimplantation genetic diagnosis. Here we describe and validate a comprehensive protocol for the molecular diagnosis of FA, based on massively parallel sequencing. We used this approach to identifyBRCA2,FANCD2,FANCIandFANCLmutations in novel unclassified FA patients.

Unexpected Fanconi Anemia Diagnosis in Patients with Bone Marrow Failure.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1056-1056
Author(s):  
Fernando O. Pinto ◽  
Thierry Leblanc ◽  
Gwenaelle Le Roux ◽  
Helene Dastot ◽  
Moema Santos ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Aplastic Anemia ◽  
Clinical Features ◽  
Fanconi Anemia ◽  
Bone Marrow Failure ◽  
Somatic Mosaicism ◽  
Chromosome Breakage ◽  
Large Set ◽  
Chromosomal Breakage ◽  
Group A

Abstract Early diagnosis of Fanconi Anemia (FA) in patients with bone marrow failure is critical for optimal clinical management. However, the remarkably high clinical variability and the potential emergence of revertant hematopoietic cells (somatic mosaicism) can obscure and delay the diagnosis of FA. Here we addressed FA diagnosis in a prospective series of adult and pediatric patients who presented with bone marrow failure without clear overall clinical picture of FA. Sixty-six patients were classified into three groups: (1) bone marrow failure likely to be congenital, based on dysmorphic features or a family history [n=18], (2) aplastic anemia likely to be idiopathic [n=32], (3) patients with intermediate clinical features not classified into the former groups [n=16]. Of note, FA patients with typical clinical features were not included in the present study. FA diagnosis was evaluated using chromosome breakage test and FANCD2 immunoblot in PHA-stimulated-PBL. In addition, skin primary fibroblasts were analysed in order to overcome potential hematopoietic FA reversion. For that purpose, and considering that chromosome breakage tests are barely efficient in fibroblasts, we used FANCD2 immunoblot and also developped a new flow cytometry test based on MMC-sensitivity in fibroblasts (to detect downstream FA/BRCA groups). Using these approaches, we detected FA in 4 previously undiagnosed patients: a 35-years old patient from the congenital-like group; a 10-years old patient presenting as an idiopathic aplastic anemia without any FA signs; and two patients from the intermediate group: a 10-years old patient with an isolated thrombocytopenia, and a 50-years old patient presenting with pancytopenia/MDS and complete hematopoietic reversion. Importantly, FA diagnosis was definitely excluded in all other patients. In conclusion, we could identify a few unexpected FA cases in a series of patients with bone marrow failure. Therefore, the comprehensive use of a large set of tests is useful for accurate FA diagnosis. Classical chromosomal breakage tests in PBL appeared to be sufficient to exclude FA in idiopathic aplastic anemia, whereas fibroblast analysis can be necessary to definitely diagnose or exclude FA in other patients.

scholarly journals International Fanconi Anemia Registry: relation of clinical symptoms to diepoxybutane sensitivity

Blood ◽  
1989 ◽  
Vol 73 (2) ◽  
pp. 391-396
Author(s):  
AD Auerbach ◽  
A Rogatko ◽  
TM Schroeder-Kurth
Keyword(s):  
Fanconi Anemia ◽  
Clinical Symptoms ◽  
Clinical Manifestations ◽  
Chromosomal Breakage ◽  
Scoring Method ◽  
Cellular Sensitivity ◽  
Progressive Pancytopenia ◽  
Clastogenic Effect ◽  
Blood Specimens ◽  
Stepwise Multivariate Logistic Regression

Fanconi anemia (FA) is characterized clinically by a progressive pancytopenia, diverse congenital abnormalities and increased predisposition to malignancy. Although a variable phenotype makes accurate diagnosis on the basis of clinical manifestations difficult in some patients, study of cellular sensitivity to the clastogenic effect of DNA cross-linking agents such as diepoxybutane (DEB) has been used to facilitate the diagnosis. Data from DEB-induced chromosomal breakage studies of 328 peripheral blood specimens from patients considered at risk for FA were analyzed using a stepwise multivariate logistic regression, in order to determine which method of representing the data best discriminated between DEB-sensitive (DEB+) and DEB-insensitive (DEB-) cases. Similar methods were applied to the data from the International Fanconi Anemia Registry (IFAR) to determine whether DEB+ and DEB- cases may be considered as distinct clinical entities, and if so, which variables provide the best discrimination between the two groups. We conclude that hypersensitivity to the clastogenic effect of DEB is a useful discriminator for FA. A simplified scoring method for classifying patients on the basis of eight clinical manifestations that are the best predictors for FA is presented. Our data indicate that the clinical diversity in FA is more widespread than previously recognized.

scholarly journals Comprehensive analysis on phenotype and genetic basis of Chinese Fanconi anemia patients: dismal outcomes call for nationwide studies

2020 ◽  
Author(s):  
Daijing Nie ◽  
Jing Zhang ◽  
Fang Wang ◽  
Wei Zhang ◽  
Lili Liu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Fanconi Anemia ◽  
Genetic Basis ◽  
Bone Marrow Failure ◽  
Clinical Manifestations ◽  
Multicenter Studies ◽  
Hematopoietic Stem ◽  
Cytogenetic Abnormalities ◽  
Number Of Patients

Abstract Background: Fanconi anemia (FA) is the most common inherited bone marrow failure (BMF) syndrome with 22 related genes identified. The ALDH2 rs671variant has been proved related to accelerate the progression of BMF in FA patients. The phenotype and genetic basis of Chinese FA patients have not been investigated yet.Methods: We analyzed the 22 FA-related genes of 63 BMF patients suspected to be FA. Clinical manifestations, morphological and cytogenetic feathers, ALDH2 genotypes, treatment, and outcomes of the definite cases were retrospectively studied.Results: A total of 24 patients were confirmed the diagnosis of FA with the median age of BMF onset was 4.5-year-old. The number of patients manifested as congenital malformations and growth retardation were 21/24 and 14/24, respectively. BM dysplasia and cytogenetic abnormalities were found in 15/23 and 10/22 patients. All the patients with abnormal karyotypes also manifested as BM dysplasia or had evident blasts. Thirty-nine different mutations were identified involving seven genes and including twenty-one novel mutations. FANCA mutations contributed to 58.33% of cases. Ten patients harboring ALDH2-G/A genotype have a significantly younger age of BMF onset (p=0.024). Within the 22 patients adhering to continuous follow-up, 18 patients underwent hematopoietic stem cell transplantations (HSCTs). During the 33.5 months of follow-up, 8/22 patients died, seven of which were HSCT-related, and one patient who did not receive HSCT died from severe infection.Conclusion: The phenotypic and genetic spectrum of Chinese FA patients is broad. Bone marrow dysplasia and cytogenetic abnormalities are prevalent and highly consistent. The overall outcome of HSCTs is disappointing. Nationwide multicenter studies are needed for the rarity and adverse outcome of this disease.

High Incidence of Fanconi Anemia in Patients with a Morphological Picture Consistent with Refractory Cytopenia of Childhood

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2780-2780
Author(s):  
Ayami Yoshimi ◽  
Charlotte M. Niemeyer ◽  
Irith Baumann ◽  
Stephan Schwarz-Furlan ◽  
Detlev Schindler ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Fanconi Anemia ◽  
Conflicts Of Interest ◽  
Bone Marrow Failure ◽  
Test Group ◽  
Clinical Feature ◽  
Chromosomal Breakage ◽  
Mild Phenotype ◽  
European Working ◽  
Chromosome Breaking

Abstract Abstract 2780 Introduction: Refractory cytopenia in childhood (RCC) is the most common subtype of myelodysplastic syndrome (MDS) in children. Differential diagnosis from inherited bone marrow failure (IBMF) such as Fanconi anemia (FA) remains an intriguing challenge, because most patients with RCC have a hypocellular bone marrow (BM) and dysplastic features in haematopoiesis are observed in both RCC and IBMF. Moreover the spectrum of phenotypic findings in FA is extremely wide. Some FA patients have a mild phenotype without malformation. The purpose of this study is to estimate the incidence of FA in an RCC cohort without a full clinical feature of FA, but subsequently diagnosed by chromosome breaking test. Patients and Methods: Between 01/2007 and 12/2010 reference pathologists of the European Working Group of MDS in Childhood (EWOG-MDS) provided a morphological report consistent with RCC in 137 children studied in Germany. Seventeen patients with hypercellular BM or abnormal karyotype, 2 patients, in whom dyskeratosis congenital was diagnosed after initial inclusion and one patient, in whom chromosome breaking test was not performed, were excluded. Results: Seven of remaining 117 patients had facial and/or skeletal anomalies typically noted in FA and one patient had a brother with FA. In these 8 patients, FA had been suspected by their local physicians (group FA-1). Nine patients (8.3%) without these typical anomalies were subsequently diagnosed of FA by chromosome breakage test (group FA-2). The diagnosis of RCC was finally made in the remaining 100 patients with negative chromosomal breakage test (group RCC). The clinical features of patients in each group are summarized in the Table. The mean corpuscular volume of red cells (MCV) was elevated (> +2SD) for ages in all patients with FA, but only 42 % in patient with RCC. In some children of group FA-2 additional non-haematological abnormalities were also observed. However, they were not evident and or typical to prompt the treating physicians to suspect FA. A few patients in the group RCC also had some physical anomalies, not specific for any of the known IBMF disorders. Possibly that other known or not yet described IBMF disorders remain uncovered in children with “de novo” RCC. Conclusion: Our results illustrate that the same haematological features and congenital anomalies can be noted in FA and RCC. More importantly, they indicate that the exclusion of FA by a chromosomal breakage test or other methods is mandatory in all patients prior to diagnosis RCC. Chromosomal breakage analysis may identify patients with FA in 8% of patients with a morphological description of RCC without a full clinical picture of FA. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Non-Hodgkin Lymphoma in Children with Primary Immunodeficiencies: Clinical Manifestations, Diagnosis, and Management, Belarusian Experience

Lymphoma ◽  
2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Alina Fedorova ◽  
Svetlana Sharapova ◽  
Taisia Mikhalevskaya ◽  
Svetlana Aleshkevich ◽  
Inna Proleskovskaya ◽  
...  
Keyword(s):  
Hodgkin Lymphoma ◽  
Clinical Manifestations ◽  
B Cell Lymphoma ◽  
Large Cell ◽  
Cell Types ◽  
Nijmegen Breakage Syndrome ◽  
Primary Immune Deficiency ◽  
Chromosomal Breakage ◽  
Hematopoietic Stem ◽  
Non Hodgkin Lymphoma

Introduction. Non-Hodgkin lymphoma (NHL) is the most frequent malignancy associated with primary immune deficiency disease (PID). We aimed to present the clinical characteristics and outcomes of Belarusian children with PID who developed NHL. Procedure. We reviewed 16 patients with PID and NHL. Eight patients had combined PID: 5—Nijmegen breakage syndrome, 1—Bloom syndrome, 1—Wiskott-Aldrich syndrome, and 1—Х-linked lymphoproliferative syndrome. Results. In 75% cases PID was diagnosed simultaneously or after the NHL was confirmed. PID-associated NHL accounted for 5.7% of all NHL and was characterized by younger median age (6.3 versus 10.0 years, P<0.05) and by prevalence of large-cell types (68.8% versus 24.5%, P<0.001). Children with combined PID had median age of 1.3 years; 5 of them developed EBV-associated diffuse large B-cell lymphoma with lung involvement. Five of 6 patients with chromosomal breakage syndrome developed T-NHL. Six patients died of infections; two died after tumor progression; one child had early relapse; two died of second NHL and one of secondary hemophagocytic syndrome. Overall, 4 children are alive and disease-free after a follow-up from 1.4 to 5.7 years. Conclusions. PID needs to be diagnosed early. Individualized chemotherapy, comprehensive supportive treatment, and hematopoietic stem cell transplantation may improve survival of children with PID and NHL.

scholarly journals Diagnosis of Fanconi Anemia: Chromosomal Breakage Analysis

Anemia ◽  
2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
Anneke B. Oostra ◽  
Aggie W. M. Nieuwint ◽  
Hans Joenje ◽  
Johan P. de Winter
Keyword(s):  
Mitomycin C ◽  
Fanconi Anemia ◽  
Autosomal Recessive ◽  
Clinical Symptoms ◽  
Bone Marrow Failure ◽  
Blood Cultures ◽  
Chromosomal Breakage ◽  
Developmental Defects ◽  
Cycle Arrest ◽  
Laboratory Protocol

Fanconi anemia (FA) is a rare inherited syndrome with diverse clinical symptoms including developmental defects, short stature, bone marrow failure, and a high risk of malignancies. Fifteen genetic subtypes have been distinguished so far. The mode of inheritance for all subtypes is autosomal recessive, except for FA-B, which is X-linked. Cells derived from FA patients are—by definition—hypersensitive to DNA cross-linking agents, such as mitomycin C, diepoxybutane, or cisplatinum, which becomes manifest as excessive growth inhibition, cell cycle arrest, and chromosomal breakage upon cellular exposure to these drugs. Here we provide a detailed laboratory protocol for the accurate assessment of the FA diagnosis as based on mitomycin C-induced chromosomal breakage analysis in whole-blood cultures. The method also enables a quantitative estimate of the degree of mosaicism in the lymphocyte compartment of the patient.

scholarly journals Comprehensive analysis on phenotype and genetic basis of Chinese Fanconi anemia patients: dismal outcomes call for nationwide studies

2020 ◽  
Author(s):  
Daijing Nie ◽  
Jing Zhang ◽  
Fang Wang ◽  
Wei Zhang ◽  
Lili Liu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Fanconi Anemia ◽  
Genetic Basis ◽  
Bone Marrow Failure ◽  
Clinical Manifestations ◽  
Multicenter Studies ◽  
Hematopoietic Stem ◽  
Cytogenetic Abnormalities ◽  
Number Of Patients

Abstract Background: Fanconi anemia (FA) is the most common inherited bone marrow failure (BMF) syndrome with 22 related genes identified. The ALDH2 rs671variant has been proved related to accelerate the progression of BMF in FA patients. The phenotype and genetic basis of Chinese FA patients have not been investigated yet.Methods: We analyzed the 22 FA-related genes of 63 BMF patients suspected to be FA. Clinical manifestations, morphological and cytogenetic feathers, ALDH2 genotypes, treatment, and outcomes of the definite cases were retrospectively studied.Results: A total of 21 patients were confirmed the diagnosis of FA with the median age of BMF onset was 4-year-old. The number of patients manifested as congenital malformations and growth retardation were 20/21 and 14/21, respectively. BM dysplasia and cytogenetic abnormalities were found in 13/20 and 8/19 patients. All the patients with abnormal karyotypes also manifested as BM dysplasia or had evident blasts. Thirty-five different mutations were identified involving six genes and including twenty novel mutations. FANCA mutations contributed to 66.67% of cases. Eight patients harboring ALDH2-G/A genotype have a significantly younger age of BMF onset (p=0.025). Within the 19 patients adhering to continuous follow-up, 15 patients underwent hematopoietic stem cell transplantations (HSCTs). During the 29 months of follow-up, 8/19 patients died, seven of which were HSCT-related, and one patient who did not receive HSCT died from severe infection.Conclusions: The phenotypic and genetic spectrum of Chinese FA patients is broad. Bone marrow dysplasia and cytogenetic abnormalities are prevalent and highly consistent. The overall outcome of HSCTs is disappointing. Nationwide multicenter studies are needed for the rarity and adverse outcome of this disease.

scholarly journals Comprehensive analysis on phenotype and genetic basis of Chinese Fanconi anemia patients: dismal outcomes call for nationwide studies

2019 ◽  
Author(s):  
Daijing Nie ◽  
Jing Zhang ◽  
Fang Wang ◽  
Wei Zhang ◽  
Lili Liu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Fanconi Anemia ◽  
Genetic Basis ◽  
Bone Marrow Failure ◽  
Clinical Manifestations ◽  
Multicenter Studies ◽  
Hematopoietic Stem ◽  
Cytogenetic Abnormalities ◽  
Number Of Patients

Abstract Background Fanconi anemia (FA) is the most common inherited bone marrow failure (BMF) syndrome with 22 related genes identified. The ALDH2 rs671variant has been proved related to accelerated progression of BMF in FA patients. The phenotype and genetic basis of Chinese FA patients have not been investigated yet.Methods We analyzed the 22 FA-related genes of 63 BMF patients suspected to be FA. Clinical manifestations, morphological and cytogenetic feathers, ALDH2 genotypes, treatment, and outcomes of the definite cases were retrospectively studied.Results 24 patients were confirmed the diagnosis of FA. The median age of BMF onset was 4.5-year old. The number of patients manifested as congenital malformations and growth retardation were 21/24 and 14/24, respectively. BM dysplasia and cytogenetic abnormalities were found in 15/23 and 10/22 patients. All the patients with abnormal karyotype also manifested as BM dysplasia or had evident blasts. Thirty-nine different variants were identified involving seven genes and including twenty-one novel variants. FANCA variants contributed to 58.33% of cases. Ten patients carried ALDH2 -G/A genotype with a significantly younger age of BMF onset ( p =0.024). Within the 22 patients adhering to continuous follow-up, 18 patients underwent hematopoietic stem cell transplantations (HSCTs). During the 33.5 months of follow-up, 8/22 patients died, seven of which were HSCT-related, and one patient who didn’t receive HSCT died from severe infection.Conclusion The phenotypic and genetic spectrum of Chinese FA patients is broad. Bone marrow dysplasia and cytogenetic abnormalities are prevalent and highly consistent. The overall outcome of HSCTs is disappointing. Nationwide multicenter studies are needed for the rarity and adverse outcome of this disease.

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