A novel diagnostic screen for defects in the Fanconi anemia pathway

Blood ◽  
2002 ◽  
Vol 100 (13) ◽  
pp. 4649-4654 ◽  
Author(s):  
Akiko Shimamura ◽  
Rocio Montes de Oca ◽  
John L. Svenson ◽  
Nicholas Haining ◽  
Lisa A. Moreau ◽  
...  
Keyword(s):  
At Risk ◽  
Bone Marrow ◽  
Fanconi Anemia ◽  
Bone Marrow Failure ◽  
Chromosomal Breakage ◽  
Retroviral Gene Transfer ◽  
Bone Marrow Failure Syndromes ◽  
Populations At Risk ◽  
Healthy Control ◽  
Or Gene

Fanconi anemia (FA) is an autosomal recessive chromosomal instability syndrome characterized by congenital abnormalities, progressive bone marrow failure, and cancer predisposition. Although patients with FA are candidates for bone marrow transplantation or gene therapy, their phenotypic heterogeneity can delay or obscure diagnosis. The current diagnostic test for FA consists of cytogenetic quantitation of chromosomal breakage in response to diepoxybutane (DEB) or mitomycin C (MMC). Recent studies have elucidated a biochemical pathway for Fanconi anemia that culminates in the monoubiquitination of the FANCD2 protein. In the current study, we develop a new rapid diagnostic and subtyping FA assay amenable for screening broad populations at risk of FA. Primary lymphocytes were assayed for FANCD2 monoubiquitination by immunoblot. The absence of the monoubiquitinated FANCD2 isoform correlated with the diagnosis of FA by DEB testing in 11 known patients with FA, 37 patients referred for possible FA, and 29 healthy control subjects. Monoubiquitination of FANCD2 was normal in other bone marrow failure syndromes and chromosomal breakage syndromes. A combination of retroviral gene transfer and FANCD2 immunoblotting provides a rapid subtyping assay for patients newly diagnosed with FA. These new FA screening assays would allow efficient testing of broad populations at risk.

Marrow Failure

Hematology ◽  
2004 ◽  
Vol 2004 (1) ◽  
pp. 318-336 ◽  
Author(s):  
Grover C. Bagby ◽  
Jeffrey M. Lipton ◽  
Elaine M. Sloand ◽  
Charles A. Schiffer
Keyword(s):  
Bone Marrow ◽  
Immunosuppressive Therapy ◽  
Fanconi Anemia ◽  
Bone Marrow Failure ◽  
Allogeneic Bone Marrow Transplantation ◽  
Dyskeratosis Congenita ◽  
Allogeneic Bone ◽  
Diagnosis And Management ◽  
Bone Marrow Failure Syndromes ◽  
Made In

Abstract New discoveries in cell biology, molecular biology and genetics have unveiled some of the pathophysiological mysteries of some of the bone marrow failure syndromes. Many of these discoveries have revealed why these syndromes show so much clinical overlap and some hold the potential for influencing the development of new therapies. In children and adults with pancytopenia and hypoplastic bone marrows proper differential diagnosis requires that some attention be directed toward defining molecular and cellular pathogenetic mechanisms because, once identified, some of these mechanisms will clearly suggest rational therapeutic approaches, treatment options that should be avoided, or both. In Section I, Drs. Jeffrey Lipton and Grover Bagby review the approach to diagnosis and management of patients with the inherited bone marrow failure syndromes, Fanconi anemia, dyskeratosis congenita, Diamond-Blackfan anemia, and the Shwachman-Diamond syndrome. Extraordinary progress has been made in identifying the genes bearing pathogenetically relevant mutations in these disorders, but slower progress has been made in defining the precise functions of the proteins these genes encode in normal cells, in part because it is increasingly obvious that the proteins are multifunctional. In practice, it is clear that in patients with dyskeratosis congenita and Fanconi anemia, the diagnosis must be considered not only in children but in adults as well. In Section II, Dr. Elaine Sloand outlines a very practical and evidence-based approach to diagnosis and management of acquired hypoplastic states emphasizing overlap between non-clonal and clonal hematopoiesis is such conditions. The pathogenesis of T lymphocyte–mediated marrow failure is presented as a clear-cut rationale for use of immunosuppressive therapy and stem cell transplantation. Practical management of patients with refractory disease with and without evidence of clonal evolution (either paroxysmal nocturnal hemoglobinuria [PNH] or myelodysplasia [MDS]) is presented. In Section III, the challenge of hypoplastic MDS is reviewed by Dr. Charles Schiffer. After reviewing the most up-to-date classification scheme, therapeutic options are reviewed, focusing largely on agents that have most recently shown some promising activity, including DNA demethylating agents, thalidomide and CC5013, arsenic trioxide, and immunosuppressive therapy. Here are also outlined the rationale and the indications for choosing allogeneic bone marrow transplantation, the only therapy with known curative potential.

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.

Constitutive elevation of serum alpha-fetoprotein in Fanconi anemia

Blood ◽  
2000 ◽  
Vol 96 (3) ◽  
pp. 859-863 ◽  
Author(s):  
Bruno Cassinat ◽  
Philippe Guardiola ◽  
Sylvie Chevret ◽  
Marie-Hélène Schlageter ◽  
Marie-Elisabeth Toubert ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Fanconi Anemia ◽  
Bone Marrow Failure ◽  
Allogeneic Bone Marrow Transplantation ◽  
Cost Effective ◽  
Alpha Fetoprotein ◽  
Allogeneic Bone ◽  
Bone Marrow Failure Syndromes ◽  
Chromosomal Breaks ◽  
Serum Alpha Fetoprotein

The diagnosis of Fanconi anemia (FA) is based on the association of congenital malformations, bone marrow failure syndrome, and hypersensitivity to chromosomal breaks induced by cross-linking agents. In the absence of typical features, the diagnosis is not easy to establish because there is no simple and cost-effective test; thus, investigators must rely on specialized analyses of chromosomal breaks. Because we observed elevated serum alpha-fetoprotein (sAFP) levels in FA patients, we investigated this parameter as a possible diagnostic tool. Serum AFP levels from 61 FA patients and 27 controls with acquired aplastic anemia or other inherited bone marrow failure syndromes were analyzed using a fluoroimmunoassay based on the TRACE technology. Serum AFP levels were significantly more elevated (P < .0001) in FA than in non-FA aplastic patients. In the detection of FA patients among patients with bone marrow failure syndromes, this assay had a sensitivity of 93% and a specificity of 100%. This elevation was not explained by liver abnormalities. Levels of sAFP were unchanged during at least 4 years of follow-up, and allogeneic bone marrow transplantation did not modify sAFP levels. Three of 4 FA patients with mosaicism as well as 5 of 6 FA patients with myelodysplastic syndrome were detected by this test. Heterozygous parents of FA patients had normal sAFP levels. Measurement of sAFP levels with this automated, cost-effective, and reproducible fluoroimmunoassay could be proposed for the preliminary diagnosis of FA whenever this disorder is suspected.

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.

Otologic manifestations of Fanconi anemia and other inherited bone marrow failure syndromes

2016 ◽  
Vol 63 (12) ◽  
pp. 2139-2145 ◽  
Author(s):  
Adedoyin Kalejaiye ◽  
Neelam Giri ◽  
Carmen C. Brewer ◽  
Christopher K. Zalewski ◽  
Kelly A. King ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Fanconi Anemia ◽  
Bone Marrow Failure ◽  
Bone Marrow Failure Syndromes

Bone Marrow Failure: A Child Is Not Just a Small Adult (But an Adult Can Have a Childhood Disease)

Hematology ◽  
2005 ◽  
Vol 2005 (1) ◽  
pp. 96-103 ◽  
Author(s):  
Blanche P. Alter
Keyword(s):  
Bone Marrow ◽  
Aplastic Anemia ◽  
Fanconi Anemia ◽  
Bone Marrow Failure ◽  
Dyskeratosis Congenita ◽  
Inherited Disorders ◽  
Adult Age ◽  
Bone Marrow Failure Syndromes ◽  
Shwachman Diamond Syndrome ◽  
High Index Of Suspicion

Abstract Aplastic anemia may be inherited or acquired. The distinction between these lies not in the age of the patient, but in the clinical and laboratory diagnoses. Adult hematologists must consider adult presentations of the inherited disorders, in order to avoid incorrect management of their patients. Physicians for adult patients must also realize that children with inherited disorders now survive to transition into their care. The major inherited bone marrow failure syndromes associated with development of pancytopenia include Fanconi anemia, dyskeratosis congenita, Shwachman-Diamond syndrome, and amegakaryocytic thrombocytopenia. The ages at presentation are highly variable, but often include individuals of adult age who have previously undiagnosed Fanconi anemia or dyskeratosis congenita. Many of the genes responsible for these disorders have been identified (12 Fanconi anemia genes, 3 dyskeratosis congenita genes, and 1 each for Shwachman-Diamond syndrome and amegakaryocytic thrombocytopenia). A high index of suspicion and specific testing of children or adults with what appears to be acquired aplastic anemia may identify inherited disorders. Correct classification of patients with aplastic anemia of any age is mandatory for their appropriate management.

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