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Akiko Shimamura - One of the best experts on this subject based on the ideXlab platform.
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recent discoveries in the molecular pathogenesis of the inherited bone Marrow Failure Syndrome fanconi anemia
Blood Reviews, 2017Co-Authors: Nicholas E Mamrak, Akiko Shimamura, Niall G HowlettAbstract:Abstract Fanconi anemia (FA) is a rare autosomal and X-linked genetic disease characterized by congenital abnormalities, progressive bone Marrow Failure (BMF), and increased cancer risk during early adulthood. The median lifespan for FA patients is approximately 33years. The proteins encoded by the FA genes function together in the FA-BRCA pathway to repair DNA damage and to maintain genome stability. Within the past two years, five new FA genes have been identified— RAD51/FANCR , BRCA1/FANCS , UBE2T/FANCT , XRCC2/FANCU , and REV7/FANCV —bringing the total number of disease-causing genes to 21. This review summarizes the discovery of these new FA genes and describes how these proteins integrate into the FA-BRCA pathway to maintain genome stability and critically prevent early-onset BMF and cancer.
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Clinical Spectrum and Molecular Pathophysiology of Shwachman-Diamond Syndrome
Blood, 2013Co-Authors: Akiko ShimamuraAbstract:Shwachman-Diamond Syndrome (SDS) is an inherited Marrow Failure Syndrome associated with exocrine pancreatic dysfunction and leukemia predisposition. SDS patients may also manifest additional non-hematologic abnormalities. Autosomal recessive mutations in the SBDS gene are found in over 90 percent of patients fitting the classical clinical phenotype of SDS. The advent of genetic testing has revealed an unexpectedly broad range of SDS phenotypes. Through the Shwachman-Diamond Syndrome Registry, we found that diagnosis may be obscured by cryptic or non-classical presentations of SDS. The timely diagnosis of SDS carries profound ramifications for medical management and treatment. We are developing assays utilizing massively parallel next generation sequencing to address this challenging diagnostic problem. Clinical applications of next generation sequencing to the diagnostic algorithm for Marrow Failure or myelodysplastic Syndrome and implications for medical treatment will be explored. Disclosures: No relevant conflicts of interest to declare.
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Impaired ribosomal subunit association in Shwachman-Diamond Syndrome
Blood, 2012Co-Authors: Nicholas Burwick, Scott A Coats, Tomoka Nakamura, Akiko ShimamuraAbstract:Shwachman-Diamond Syndrome (SDS) is an autosomal-recessive Marrow Failure Syndrome with a predisposition to leukemia. SDS patients harbor biallelic mutations in the SBDS gene, resulting in low levels of SBDS protein. Data from nonhuman models demonstrate that the SBDS protein facilitates the release of eIF6, a factor that prevents ribosome joining. The complete abrogation of Sbds expression in these models results in severe cellular and lethal physiologic abnormalities that differ from the human disease phenotype. Because human SDS cells are characterized by partial rather than complete loss of SBDS expression, we interrogated SDS patient cells for defects in ribosomal assembly. SDS patient cells exhibit altered ribosomal profiles and impaired association of the 40S and 60S subunits. Introduction of a wild-type SBDS cDNA into SDS patient cells corrected the ribosomal association defect, while patient-derived SBDS point mutants only partially improved subunit association. Knockdown of eIF6 expression improved ribosomal subunit association but did not correct the hematopoietic defect of SBDS-deficient cells. In summary, we demonstrate an SBDS-dependent ribosome maturation defect in SDS patient cells. The role of ribosomal subunit joining in Marrow Failure warrants further investigation.
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Breast cancer in a case of Shwachman Diamond Syndrome.
Pediatric Blood & Cancer, 2011Co-Authors: Sharon Singh, Nora J. Morgenstern, Ihsane Ouansafi, Wan Ip, Adrianna Vlachos, Peter R. Durie, Akiko Shimamura, Johanna M Rommens, Jeffrey M. LiptonAbstract:Shwachman Diamond Syndrome (SDS) is a rare inherited bone Marrow Failure Syndrome (IBMFS) characterized by neutropenia, exocrine pancreatic dysfunction, and cancer predisposition. Patients are at risk for myelodysplastic Syndrome (MDS) and acute myelogenous leukemia (AML) but, unlike other IBMFS, there have been no reported cases of solid tumors. We report a novel case of a solid tumor in a patient with SDS and biallelic mutations in the Shwachman Bodian Diamond Syndrome gene (SBDS). Whether the development of breast cancer in this patient is due to SDS or an isolated case due to unknown factors requires further study. Pediatr Blood Cancer 2012; 59: 945–946. © 2011 Wiley Periodicals, Inc.
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sbds protein expression patterns in the bone Marrow
Pediatric Blood & Cancer, 2010Co-Authors: Trisha E Wong, Monica L Calicchio, Akiko Shimamura, Mark D Fleming, Marian H. HarrisAbstract:Shwachman–Diamond Syndrome (SDS) is an inherited bone Marrow Failure Syndrome caused by biallelic SBDS gene mutations. Here we examined SBDS protein levels in human bone Marrow. SBDS protein expression was high in neutrophil progenitors, megakaryocytes, plasma cells, and osteoblasts. In contrast, SBDS protein levels were low in all hematopoietic cell lineages from patients harboring the common SBDS mutations. We conclude that SBDS protein levels vary widely between specific Marrow lineages. Uniformly low SBDS protein expression levels distinguish the majority of SDS patients from controls or other Marrow Failure Syndromes. Pediatr Blood Cancer. 2010;55:546–549. © 2010 Wiley-Liss, Inc.
Blanche P Alter - One of the best experts on this subject based on the ideXlab platform.
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cancer in the national cancer institute inherited bone Marrow Failure Syndrome cohort after fifteen years of follow up
Haematologica, 2018Co-Authors: Blanche P Alter, Neelam Giri, Sharon A. Savage, Philip S RosenbergAbstract:The National Cancer Institute Inherited Bone Marrow Failure Syndromes Cohort enrolls patients with the four major Syndromes: Fanconi anemia, dyskeratosis congenita, Diamond-Blackfan anemia, and Shwachman-Diamond Syndrome, and follows them with a common comprehensive protocol. The current analysis includes more than double the numbers of patients and person-years since our first report, published in 2010. Patients with Fanconi anemia and dyskeratosis congenita developed head and neck and anogenital squamous cell carcinomas at rates that were hundreds-fold greater than those of the general population. In competing risk analyses the cumulative incidence of severe bone Marrow Failure, leading to stem cell transplantation or death, was more than 70% by age 60. Patients with Diamond-Blackfan anemia developed lung, colon, and cervical cancer at rates greater than those of the general population. The cumulative incidence of severe bone Marrow Failure in those with Diamond-Blackfan anemia was 50% by age 60. The smaller group, with Shwachman-Diamond Syndrome, have not as yet developed a significant number of solid tumors, but 40% developed bone Marrow Failure by age 50. The risk of solid tumors following stem cell transplantation in Fanconi anemia and in dyskeratosis congenita was significantly higher than in non-transplanted patients. There was no clear association of genotype with cancer in any of the Syndromes. Cancer was most common in Fanconi anemia, followed by dyskeratosis congenita; Diamond-Blackfan anemia and Shwachman-Diamond Syndrome are less cancer-prone, but nonetheless all patients are at increased risks of bone Marrow Failure and specific cancers. clinicaltrials.gov Identifier: 00027274.
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Pregnancies in patients with inherited bone Marrow Failure Syndromes in the NCI cohort.
Blood, 2017Co-Authors: Neelam Giri, Sharon A. Savage, Pamela Stratton, Blanche P AlterAbstract:To the editor: We read with great interest the recent letter in Blood , by Gansner et al, on the topic of pregnancies in patients with an inherited bone Marrow Failure Syndrome (IBMFS).[1][1] We agree that these rare patients have reduced numbers and complicated pregnancies, and we think that our
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comparison of chromosome breakage in non mosaic and mosaic patients with fanconi anemia relatives and patients with other inherited bone Marrow Failure Syndromes
Cytogenetic and Genome Research, 2014Co-Authors: John H Fargo, Neelam Giri, Sharon A. Savage, Andrzej Rochowski, Susan B Olson, Blanche P AlterAbstract:Fanconi anemia (FA) is a rare inherited bone Marrow Failure Syndrome (IBMFS). Affected individuals must be distinguished from relatives, patients with mosaicism must be identified, and patients with other IBMFS classified as non-FA. The diagnostic feature of FA is increased chromosomal breakage in blood lymphocytes cultured with diepoxybutane or mitomycin C. Here, we sought a method to uniquely identify patients with FA with mosaicism, using cells from participants in the National Cancer Institute IBMFS cohort. Lymphocytes were treated with diepoxybutane or mitomycin C, and metaphases scored for breaks and radials. Analyses included the percentage of cells with any aberration, breaks per cell, and breaks per aberrant cell. There were 26 patients with FA (4 mosaics), 46 FA relatives, and 62 patients with a non-FA IBMFS. By all analytic methods, patients with FA were abnormal compared with other groups. Those with FA mosaicism had more breakage than relatives or patients with non-FA IBMFS, but there was some individual overlap. The choices of clastogen are laboratory-dependent, but there was no method or analysis of lymphocytes that clearly distinguished all individuals mosaic for FA from relatives or patients with other IBMFS. Thus, genotyping remains the best method for providing absolute clarity.
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Reduced Serum Levels of Anti-Müllerian Hormone in Females With Inherited Bone Marrow Failure Syndromes
The Journal of clinical endocrinology and metabolism, 2014Co-Authors: Martha M. Sklavos, Neelam Giri, Blanche P Alter, Sharon A. Savage, Pamela Stratton, Ligia A. PintoAbstract:Context: Previously, reduced levels of anti-Mullerian hormone (AMH), a circulating marker of ovarian reserve, were found in females with Fanconi anemia (FA). FA, dyskeratosis congenita (DC), and Diamond-Blackfan anemia (DBA) are inherited bone Marrow Failure Syndromes (IBMFS) associated with high risks of bone Marrow Failure, leukemia, and solid tumors. Objective: The objective of the study was to assess AMH levels in females with DC or DBA. Design and Setting: This observational study used the National Cancer Institute's inherited bone Marrow Failure Syndrome cohort at the National Institutes of Health Clinical Center. Participants: The study included females with DC, unaffected female relatives of patients with DC, females with DBA, unaffected female relatives of patients with DBA, and unrelated healthy female volunteers younger than 41 years of age. Main Outcome measure: Serum AMH levels were measured. Results: Females with DC had significantly lower levels of AMH (median 0.55 ng/mL) compared with unaf...
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erythrocyte adenosine deaminase diagnostic value for diamond blackfan anaemia
British Journal of Haematology, 2013Co-Authors: John H Fargo, Neelam Giri, Blanche P Alter, Sharon A. Savage, Christian P Kratz, Carolyn Wong, Karen Backer, Bertil GladerAbstract:Diamond-Blackfan anaemia (DBA) is an inherited bone Marrow Failure Syndrome (IBMFS) characterized by red cell aplasia. Mutations in ribosomal genes are found in more than 50% of cases. Elevated erythrocyte adenosine deaminase (eADA) was first noted in DBA in 1983. In this study we determined the value of eADA for the diagnosis of DBA compared with other IBMFS; the association of eADA in DBA with age, gender or other haematological parameters; and the association with known DBA-related gene mutations. For the diagnosis of DBA compared with non-DBA patients with other bone Marrow Failure Syndromes, eADA had a sensitivity of 84%, specificity 95%, and positive and negative predictive values of 91%. In patients with DBA there was no association between eADA and gender, age, or other haematological parameters. Erythrocyte ADA segregated with, as well as independent of, known DBA gene mutations. While eADA was an excellent confirmatory test for DBA, 16% of patients with classical clinical DBA had a normal eADA.
Neelam Giri - One of the best experts on this subject based on the ideXlab platform.
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cancer in the national cancer institute inherited bone Marrow Failure Syndrome cohort after fifteen years of follow up
Haematologica, 2018Co-Authors: Blanche P Alter, Neelam Giri, Sharon A. Savage, Philip S RosenbergAbstract:The National Cancer Institute Inherited Bone Marrow Failure Syndromes Cohort enrolls patients with the four major Syndromes: Fanconi anemia, dyskeratosis congenita, Diamond-Blackfan anemia, and Shwachman-Diamond Syndrome, and follows them with a common comprehensive protocol. The current analysis includes more than double the numbers of patients and person-years since our first report, published in 2010. Patients with Fanconi anemia and dyskeratosis congenita developed head and neck and anogenital squamous cell carcinomas at rates that were hundreds-fold greater than those of the general population. In competing risk analyses the cumulative incidence of severe bone Marrow Failure, leading to stem cell transplantation or death, was more than 70% by age 60. Patients with Diamond-Blackfan anemia developed lung, colon, and cervical cancer at rates greater than those of the general population. The cumulative incidence of severe bone Marrow Failure in those with Diamond-Blackfan anemia was 50% by age 60. The smaller group, with Shwachman-Diamond Syndrome, have not as yet developed a significant number of solid tumors, but 40% developed bone Marrow Failure by age 50. The risk of solid tumors following stem cell transplantation in Fanconi anemia and in dyskeratosis congenita was significantly higher than in non-transplanted patients. There was no clear association of genotype with cancer in any of the Syndromes. Cancer was most common in Fanconi anemia, followed by dyskeratosis congenita; Diamond-Blackfan anemia and Shwachman-Diamond Syndrome are less cancer-prone, but nonetheless all patients are at increased risks of bone Marrow Failure and specific cancers. clinicaltrials.gov Identifier: 00027274.
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Pregnancies in patients with inherited bone Marrow Failure Syndromes in the NCI cohort.
Blood, 2017Co-Authors: Neelam Giri, Sharon A. Savage, Pamela Stratton, Blanche P AlterAbstract:To the editor: We read with great interest the recent letter in Blood , by Gansner et al, on the topic of pregnancies in patients with an inherited bone Marrow Failure Syndrome (IBMFS).[1][1] We agree that these rare patients have reduced numbers and complicated pregnancies, and we think that our
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comparison of chromosome breakage in non mosaic and mosaic patients with fanconi anemia relatives and patients with other inherited bone Marrow Failure Syndromes
Cytogenetic and Genome Research, 2014Co-Authors: John H Fargo, Neelam Giri, Sharon A. Savage, Andrzej Rochowski, Susan B Olson, Blanche P AlterAbstract:Fanconi anemia (FA) is a rare inherited bone Marrow Failure Syndrome (IBMFS). Affected individuals must be distinguished from relatives, patients with mosaicism must be identified, and patients with other IBMFS classified as non-FA. The diagnostic feature of FA is increased chromosomal breakage in blood lymphocytes cultured with diepoxybutane or mitomycin C. Here, we sought a method to uniquely identify patients with FA with mosaicism, using cells from participants in the National Cancer Institute IBMFS cohort. Lymphocytes were treated with diepoxybutane or mitomycin C, and metaphases scored for breaks and radials. Analyses included the percentage of cells with any aberration, breaks per cell, and breaks per aberrant cell. There were 26 patients with FA (4 mosaics), 46 FA relatives, and 62 patients with a non-FA IBMFS. By all analytic methods, patients with FA were abnormal compared with other groups. Those with FA mosaicism had more breakage than relatives or patients with non-FA IBMFS, but there was some individual overlap. The choices of clastogen are laboratory-dependent, but there was no method or analysis of lymphocytes that clearly distinguished all individuals mosaic for FA from relatives or patients with other IBMFS. Thus, genotyping remains the best method for providing absolute clarity.
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Reduced Serum Levels of Anti-Müllerian Hormone in Females With Inherited Bone Marrow Failure Syndromes
The Journal of clinical endocrinology and metabolism, 2014Co-Authors: Martha M. Sklavos, Neelam Giri, Blanche P Alter, Sharon A. Savage, Pamela Stratton, Ligia A. PintoAbstract:Context: Previously, reduced levels of anti-Mullerian hormone (AMH), a circulating marker of ovarian reserve, were found in females with Fanconi anemia (FA). FA, dyskeratosis congenita (DC), and Diamond-Blackfan anemia (DBA) are inherited bone Marrow Failure Syndromes (IBMFS) associated with high risks of bone Marrow Failure, leukemia, and solid tumors. Objective: The objective of the study was to assess AMH levels in females with DC or DBA. Design and Setting: This observational study used the National Cancer Institute's inherited bone Marrow Failure Syndrome cohort at the National Institutes of Health Clinical Center. Participants: The study included females with DC, unaffected female relatives of patients with DC, females with DBA, unaffected female relatives of patients with DBA, and unrelated healthy female volunteers younger than 41 years of age. Main Outcome measure: Serum AMH levels were measured. Results: Females with DC had significantly lower levels of AMH (median 0.55 ng/mL) compared with unaf...
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erythrocyte adenosine deaminase diagnostic value for diamond blackfan anaemia
British Journal of Haematology, 2013Co-Authors: John H Fargo, Neelam Giri, Blanche P Alter, Sharon A. Savage, Christian P Kratz, Carolyn Wong, Karen Backer, Bertil GladerAbstract:Diamond-Blackfan anaemia (DBA) is an inherited bone Marrow Failure Syndrome (IBMFS) characterized by red cell aplasia. Mutations in ribosomal genes are found in more than 50% of cases. Elevated erythrocyte adenosine deaminase (eADA) was first noted in DBA in 1983. In this study we determined the value of eADA for the diagnosis of DBA compared with other IBMFS; the association of eADA in DBA with age, gender or other haematological parameters; and the association with known DBA-related gene mutations. For the diagnosis of DBA compared with non-DBA patients with other bone Marrow Failure Syndromes, eADA had a sensitivity of 84%, specificity 95%, and positive and negative predictive values of 91%. In patients with DBA there was no association between eADA and gender, age, or other haematological parameters. Erythrocyte ADA segregated with, as well as independent of, known DBA gene mutations. While eADA was an excellent confirmatory test for DBA, 16% of patients with classical clinical DBA had a normal eADA.
Inderjeet Dokal - One of the best experts on this subject based on the ideXlab platform.
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ercc6l2 mutations link a distinct bone Marrow Failure Syndrome to dna repair and mitochondrial function
American Journal of Human Genetics, 2014Co-Authors: Hemanth Tummala, Michael Kirwan, Amanda J Walne, Upal Hossain, N Jackson, Corinne Pondarre, Vincent Plagnol, Tom Vulliamy, Inderjeet DokalAbstract:Exome sequencing was performed in three index cases with bone Marrow Failure and neurological dysfunction and whose parents are first-degree cousins. Homozygous truncating mutations were identified in ERCC6L2 in two of the individuals. Both of these mutations affect the subcellular localization and stability of ERCC6L2. We show here that knockdown of ERCC6L2 in human A549 cells significantly reduced their viability upon exposure to the DNA-damaging agents mitomycin C and Irofulven, but not etoposide and camptothecin, suggesting a role in nucleotide excision repair. ERCC6L2-knockdown cells also displayed H2AX phosphorylation, which significantly increased upon genotoxic stress, suggesting an early DNA-damage response. Intriguingly, ERCC6L2 was seen to translocate to the mitochondria and the nucleus in response to DNA damage, and ERCC6L2 knockdown induced intracellular reactive oxygen species (ROS). Treatment with the ROS scavenger N-acetyl cysteine attenuated the Irofulven-induced cytotoxicity in ERCC6L2-knockdown cells and abolished ERCCGL2 traffic to the mitochondria and nucleus in response to this DNA-damaging agent. Collectively, these observations identify a distinct bone-Marrow-Failure Syndrome due to mutations in ERCC6L2, a gene implicated in DNA repair and mitochondrial function.
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Hepatitis-associated aplastic anemia presenting as a familial bone Marrow Failure Syndrome.
Journal of pediatric hematology oncology, 2009Co-Authors: Vicky R. Breakey, Peter M Lansdorp, Stephen Meyn, Christopher Allen, Inderjeet Dokal, Oussama Abla, Yigal DrorAbstract:Hepatitis-associated aplastic anemia is a well-described entity after idiopathic fulminant hepatic Failure. The hematologic disease ranges from mild-to-severe aplastic anemia and the cause of the disease is unknown. We describe 2 siblings with bone Marrow Failure. The older child presented with idiopathic fulminant hepatic Failure and an early onset of rapidly progressive severe aplastic anemia that developed into myelodysplastic Syndrome postliver transplantation. In the process of family screening to locate a donor for hematopoietic stem cell transplantation, the younger sibling was found to have hypocellular bone Marrow and later developed acute lymphoblastic leukemia. These familial cases raise the possibility of an inherited bone Marrow Failure Syndrome and suggest that severe hepatitis-associated aplastic anemia may not be always an acquired condition.
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telomerase reverse transcriptase homozygous mutations in autosomal recessive dyskeratosis congenita and hoyeraal hreidarsson Syndrome
Blood, 2007Co-Authors: Anna Marrone, Michael Kirwan, Amanda J Walne, Tom Vulliamy, Hannah Tamary, Yuka Masunari, Richard Beswick, Inderjeet DokalAbstract:Dyskeratosis congenita (DC) is a multisystem bone Marrow Failure Syndrome characterized by a triad of mucocutaneous abnormalities and an increased predisposition to malignancy. X-linked DC is due to mutations in DKC1, while heterozygous mutations in TERC (telomerase RNA component) and TERT (telomerase reverse transcriptase) have been found in autosomal dominant DC. Many patients with DC remain uncharacterized, particularly families displaying autosomal recessive (AR) inheritance. We have now identified novel homozygous TERT mutations in 2 unrelated consanguineous families, where the index cases presented with classical DC or the more severe variant, Hoyeraal-Hreidarsson (HH) Syndrome. These TERT mutations resulted in reduced telomerase activity and extremely short telomeres. As these mutations are homozygous, these patients are predicted to have significantly reduced telomerase activity in vivo. Interestingly, in contrast to patients with heterozygous TERT mutations or hemizygous DKC1 mutations, these 2 homozygous TERT patients were observed to have higher-than-expected TERC levels compared with controls. Collectively, the findings from this study demonstrate that homozygous TERT mutations, resulting in a pure but severe telomerase deficiency, produce a phenotype of classical AR-DC and its severe variant, the HH Syndrome.
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mutations in dyskeratosis congenita their impact on telomere length and the diversity of clinical presentation
Blood, 2006Co-Authors: Tom Vulliamy, Philip J. Mason, Amanda J Walne, Anna Marrone, Stuart W Knight, Inderjeet DokalAbstract:The two genes mutated in the bone Marrow Failure Syndrome dyskeratosis congenita (DC) both encode components of the telomerase complex responsible for maintaining the ends of chromosomes in stem cells and in the germ line. In reviewing the mutation profile that is found in DC, we describe 9 novel mutations in the DKC1 gene and 3 novel TERC mutations responsible for the X-linked and autosomal dominant forms of the disease, respectively, but find that two thirds of the families do not have mutations in either of these genes. In a significant subset of these uncharacterized families, the index case presents with severe disease previously defined as the Hoyeraal Hreidarsson (HH) Syndrome. The diverse clinical phenotype seen in patients with X-linked DC is not explained by the different amino acid substitutions: Presentation of the recurrent A353V substitution ranges from classic DC to the severe HH variant. However, we do see that patients with HH have significantly shorter telomeres than those with a relatively mild presentation. In the new families described with TERC mutations, there is further evidence of disease anticipation associated with shorter telomeres in the younger generations. This study highlights the considerable genetic and phenotypic diversity of DC.
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disease anticipation is associated with progressive telomere shortening in families with dyskeratosis congenita due to mutations in terc
Nature Genetics, 2004Co-Authors: Tom Vulliamy, Philip J. Mason, Amanda J Walne, Anna Marrone, Richard Szydlo, Inderjeet DokalAbstract:Telomerase is a ribonucleoprotein complex that is required to synthesize DNA repeats at the ends of each chromosome. The RNA component of this reverse transcriptase is mutated in the bone Marrow Failure Syndrome autosomal dominant dyskeratosis congenita. Here we show that disease anticipation is observed in families with this disease and that this is associated with progressive telomere shortening.
Sharon A. Savage - One of the best experts on this subject based on the ideXlab platform.
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cancer in the national cancer institute inherited bone Marrow Failure Syndrome cohort after fifteen years of follow up
Haematologica, 2018Co-Authors: Blanche P Alter, Neelam Giri, Sharon A. Savage, Philip S RosenbergAbstract:The National Cancer Institute Inherited Bone Marrow Failure Syndromes Cohort enrolls patients with the four major Syndromes: Fanconi anemia, dyskeratosis congenita, Diamond-Blackfan anemia, and Shwachman-Diamond Syndrome, and follows them with a common comprehensive protocol. The current analysis includes more than double the numbers of patients and person-years since our first report, published in 2010. Patients with Fanconi anemia and dyskeratosis congenita developed head and neck and anogenital squamous cell carcinomas at rates that were hundreds-fold greater than those of the general population. In competing risk analyses the cumulative incidence of severe bone Marrow Failure, leading to stem cell transplantation or death, was more than 70% by age 60. Patients with Diamond-Blackfan anemia developed lung, colon, and cervical cancer at rates greater than those of the general population. The cumulative incidence of severe bone Marrow Failure in those with Diamond-Blackfan anemia was 50% by age 60. The smaller group, with Shwachman-Diamond Syndrome, have not as yet developed a significant number of solid tumors, but 40% developed bone Marrow Failure by age 50. The risk of solid tumors following stem cell transplantation in Fanconi anemia and in dyskeratosis congenita was significantly higher than in non-transplanted patients. There was no clear association of genotype with cancer in any of the Syndromes. Cancer was most common in Fanconi anemia, followed by dyskeratosis congenita; Diamond-Blackfan anemia and Shwachman-Diamond Syndrome are less cancer-prone, but nonetheless all patients are at increased risks of bone Marrow Failure and specific cancers. clinicaltrials.gov Identifier: 00027274.
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Pregnancies in patients with inherited bone Marrow Failure Syndromes in the NCI cohort.
Blood, 2017Co-Authors: Neelam Giri, Sharon A. Savage, Pamela Stratton, Blanche P AlterAbstract:To the editor: We read with great interest the recent letter in Blood , by Gansner et al, on the topic of pregnancies in patients with an inherited bone Marrow Failure Syndrome (IBMFS).[1][1] We agree that these rare patients have reduced numbers and complicated pregnancies, and we think that our
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comparison of chromosome breakage in non mosaic and mosaic patients with fanconi anemia relatives and patients with other inherited bone Marrow Failure Syndromes
Cytogenetic and Genome Research, 2014Co-Authors: John H Fargo, Neelam Giri, Sharon A. Savage, Andrzej Rochowski, Susan B Olson, Blanche P AlterAbstract:Fanconi anemia (FA) is a rare inherited bone Marrow Failure Syndrome (IBMFS). Affected individuals must be distinguished from relatives, patients with mosaicism must be identified, and patients with other IBMFS classified as non-FA. The diagnostic feature of FA is increased chromosomal breakage in blood lymphocytes cultured with diepoxybutane or mitomycin C. Here, we sought a method to uniquely identify patients with FA with mosaicism, using cells from participants in the National Cancer Institute IBMFS cohort. Lymphocytes were treated with diepoxybutane or mitomycin C, and metaphases scored for breaks and radials. Analyses included the percentage of cells with any aberration, breaks per cell, and breaks per aberrant cell. There were 26 patients with FA (4 mosaics), 46 FA relatives, and 62 patients with a non-FA IBMFS. By all analytic methods, patients with FA were abnormal compared with other groups. Those with FA mosaicism had more breakage than relatives or patients with non-FA IBMFS, but there was some individual overlap. The choices of clastogen are laboratory-dependent, but there was no method or analysis of lymphocytes that clearly distinguished all individuals mosaic for FA from relatives or patients with other IBMFS. Thus, genotyping remains the best method for providing absolute clarity.
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Reduced Serum Levels of Anti-Müllerian Hormone in Females With Inherited Bone Marrow Failure Syndromes
The Journal of clinical endocrinology and metabolism, 2014Co-Authors: Martha M. Sklavos, Neelam Giri, Blanche P Alter, Sharon A. Savage, Pamela Stratton, Ligia A. PintoAbstract:Context: Previously, reduced levels of anti-Mullerian hormone (AMH), a circulating marker of ovarian reserve, were found in females with Fanconi anemia (FA). FA, dyskeratosis congenita (DC), and Diamond-Blackfan anemia (DBA) are inherited bone Marrow Failure Syndromes (IBMFS) associated with high risks of bone Marrow Failure, leukemia, and solid tumors. Objective: The objective of the study was to assess AMH levels in females with DC or DBA. Design and Setting: This observational study used the National Cancer Institute's inherited bone Marrow Failure Syndrome cohort at the National Institutes of Health Clinical Center. Participants: The study included females with DC, unaffected female relatives of patients with DC, females with DBA, unaffected female relatives of patients with DBA, and unrelated healthy female volunteers younger than 41 years of age. Main Outcome measure: Serum AMH levels were measured. Results: Females with DC had significantly lower levels of AMH (median 0.55 ng/mL) compared with unaf...
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erythrocyte adenosine deaminase diagnostic value for diamond blackfan anaemia
British Journal of Haematology, 2013Co-Authors: John H Fargo, Neelam Giri, Blanche P Alter, Sharon A. Savage, Christian P Kratz, Carolyn Wong, Karen Backer, Bertil GladerAbstract:Diamond-Blackfan anaemia (DBA) is an inherited bone Marrow Failure Syndrome (IBMFS) characterized by red cell aplasia. Mutations in ribosomal genes are found in more than 50% of cases. Elevated erythrocyte adenosine deaminase (eADA) was first noted in DBA in 1983. In this study we determined the value of eADA for the diagnosis of DBA compared with other IBMFS; the association of eADA in DBA with age, gender or other haematological parameters; and the association with known DBA-related gene mutations. For the diagnosis of DBA compared with non-DBA patients with other bone Marrow Failure Syndromes, eADA had a sensitivity of 84%, specificity 95%, and positive and negative predictive values of 91%. In patients with DBA there was no association between eADA and gender, age, or other haematological parameters. Erythrocyte ADA segregated with, as well as independent of, known DBA gene mutations. While eADA was an excellent confirmatory test for DBA, 16% of patients with classical clinical DBA had a normal eADA.