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1.  Transcriptome Analysis of the Zebrafish Model of Diamond-Blackfan Anemia from RPS19 Deficiency via p53-Dependent and -Independent Pathways 
PLoS ONE  2013;8(8):e71782.
Diamond-Blackfan anemia (DBA) is a rare inherited bone marrow failure syndrome that is characterized by pure red-cell aplasia and associated physical deformities. It has been proven that defects of ribosomal proteins can lead to this disease and that RPS19 is the most frequently mutated gene in DBA patients. Previous studies suggest that p53-dependent genes and pathways play important roles in RPS19-deficient embryos. However, whether there are other vital factors linked to DBA has not been fully clarified. In this study, we compared the whole genome RNA-Seq data of zebrafish embryos injected with RPS19 morpholino (RPS19 MO), RPS19 and p53 morpholino simultaneously (RPS19+p53 MO) and control morpholino (control). We found that genes enriched in the functions of hematological systems, nervous system development and skeletal and muscular disorders had significant differential expression in RPS19 MO embryos compared with controls. Co-inhibition of p53 partially alleviates the abnormalities for RPS19-deficient embryos. However, the hematopoietic genes, which were down-regulated significantly in RPS19 MO embryos, were not completely recovered by the co-inhibition of p53. Furthermore, we identified the genome-wide p53-dependent and -independent genes and pathways. These results indicate that not only p53 family members but also other factors have important impacts on RPS19-deficient embryos. The detection of potential pathogenic genes and pathways provides us a new paradigm for future research on DBA, which is a systematic and complex hereditary disease.
doi:10.1371/journal.pone.0071782
PMCID: PMC3747179  PMID: 23990987
2.  Progress towards Mechanism-Based Treatment for Diamond-Blackfan Anemia 
The Scientific World Journal  2012;2012:184362.
Diamond-Blackfan anemia (DBA) is a congenital erythroid hypoplastic anemia, characterized by macrocytic anemia, reticulocytopenia, and severely reduced numbers of erythroid precursors in the bone marrow. For more than fifty years, glucocorticoids have remained the main option for pharmacological treatment of DBA. While continuous glucocorticoid administration increases hemoglobin levels in a majority of DBA patients, it also causes severe side effects. There is therefore a great need for more specific and effective treatments to boost or replace the use of glucocorticoids. Over the years, many alternative therapies have been tried out, but most of them have shown to be ineffective. Here we review previous and current attempts to develop such alternative therapies for DBA. We further discuss how emerging knowledge regarding the pathological mechanism in DBA and the therapeutic mechanism of glucocorticoids treatment may reveal novel drug targets for DBA treatment.
doi:10.1100/2012/184362
PMCID: PMC3349117  PMID: 22619618
3.  Diamond Blackfan Anemia at the Crossroad between Ribosome Biogenesis and Heme Metabolism 
Advances in Hematology  2010;2010:790632.
Diamond-Blackfan anemia (DBA) is a rare, pure red-cell aplasia that presents during infancy. Approximately 40% of cases are associated with other congenital defects, particularly malformations of the upper limb or craniofacial region. Mutations in the gene coding for the ribosomal protein RPS19 have been identified in 25% of patients with DBA, with resulting impairment of 18S rRNA processing and 40S ribosomal subunit formation. Moreover, mutations in other ribosomal protein coding genes account for about 25% of other DBA cases. Recently, the analysis of mice from which the gene coding for the heme exporter Feline Leukemia Virus subgroup C Receptor (FLVCR1) is deleted suggested that this gene may be involved in the pathogenesis of DBA. FLVCR1-null mice show a phenotype resembling that of DBA patients, including erythroid failure and malformations. Interestingly, some DBA patients have disease linkage to chromosome 1q31, where FLVCR1 is mapped. Moreover, it has been reported that cells from DBA patients express alternatively spliced isoforms of FLVCR1 which encode non-functional proteins. Herein, we review the known roles of RPS19 and FLVCR1 in ribosome function and heme metabolism respectively, and discuss how the deficiency of a ribosomal protein or of a heme exporter may result in the same phenotype.
doi:10.1155/2010/790632
PMCID: PMC2864449  PMID: 20454576
4.  Obsessive compulsive disorder comorbidity in DBA 
Diamond-Blackfan Anemia (DBA) is a congenital erythroid aplasia characterized as a normochromic macrocytic anemia with a selective deficiency in red blood cell precursors in otherwise normocelullar bone marrow. DBA is known to be associated with mental retardation and learning disabilities. Although comorbidities with other psychiatric conditions have not been reported in the existing literature, we report in this paper a case of a DBA patient with previously undiagnosed comorbidity of obsessive compulsive disorder (OCD), successfully treated with sertaline 200 mg/day and valproic acid 600 mg/day. This case of comorbid presentation has clinical, therapeutic and pathophysiological implications. Given the difficulty of distinguishing among mental retardation, learning disabilities and OCD and the importance of precocious diagnosis in treating OCD especially since there are treatment methods interfering with anemia symptoms, physicians should adapt an adequate screening tool treating a child with DBA and comorbid mental disorder.
doi:10.1186/1745-0179-4-6
PMCID: PMC2322982  PMID: 18331650
5.  Defective Ribosomal Protein Gene Expression Alters Transcription, Translation, Apoptosis, and Oncogenic Pathways in Diamond-Blackfan Anemia 
Stem Cells (Dayton, Ohio)  2006;24(9):2034-2044.
Diamond-Blackfan anemia (DBA) is a broad developmental disease characterized by anemia, bone marrow (BM) erythroblastopenia, and an increased incidence of malignancy. Mutations in ribosomal protein gene S19 (RPS19) are found in ~25% of DBA patients; however, the role of RPS19 in the pathogenesis of DBA remains unknown. Using global gene expression analysis, we compared highly purified multipotential, erythroid, and myeloid BM progenitors from RPS19 mutated and control individuals. We found several ribosomal protein genes downregulated in all DBA progenitors. Apoptosis genes, such as TNFRSF10B and FAS, transcriptional control genes, including the erythropoietic transcription factor MYB (encoding c-myb), and translational genes were greatly dysregulated, mostly in diseased erythroid cells. Cancer-related genes, including RAS family oncogenes and tumor suppressor genes, were significantly dysregulated in all diseased progenitors. In addition, our results provide evidence that RPS19 mutations lead to codownregulation of multiple ribosomal protein genes, as well as downregulation of genes involved in translation in DBA cells. In conclusion, the altered expression of cancer-related genes suggests a molecular basis for malignancy in DBA. Downregulation of c-myb expression, which causes complete failure of fetal liver erythropoiesis in knockout mice, suggests a link between RPS19 mutations and reduced erythropoiesis in DBA.
doi:10.1634/stemcells.2005-0554
PMCID: PMC3372914  PMID: 16741228
Diamond-Blackfan anemia; Bone marrow failure; Global gene expression; Ribosomal protein genes; Apoptosis Cancer
6.  Diamond-Blackfan anemia, ribosome and erythropoiesis 
Diamond-Blackfan anemia is a rare inherited bone marrow failure syndrome (5 to 7 cases/million live births) characterized by an are generative, usually macrocytic anemia with an absence or less than 5% of erythroid precursors (erythroblastopenia) in an otherwise normal bone marrow. The platelet and the white cell counts are usually normal but neutropenia, thrombopenia or thrombocytosis have been noted at diagnosis. In 40 to 50% of DBA patients, congenital abnormalities mostly in the cephalic area and in thumbs and upper limbs have been described. Recent analysis did show a phenotype/genotype correlation. Congenital erythroblastopenia of DBA is the first human disease identified to result from defects in ribosomal biogenesis. The first ribosomal gene involved in DBA, ribosomal protein (RP) gene S19 (RPS19 gene), was identified in 1999. Subsequently, mutations in 12 other RP genes out of a total of 78 RP genes have been identified in DBA. All RP gene mutations described to date are heterozygous and dominant inheritance has been documented in 40 to 45% of affected individuals. As RP mutations are yet to be identified in approximately 50% of DBA cases, it is likely that other yet to be identified genes involved in ribosomal biogenesis or other pathways may be responsible for DBA phenotype.
doi:10.1016/j.tracli.2010.06.001
PMCID: PMC3699172  PMID: 20655265
Diamond-Blackfan anemia; erythroblastopenia; ribosome; p53; apoptosis
7.  Diagnosing and Treating Diamond Blackfan Anemia: Results of an International Clinical Consensus Conference 
British journal of haematology  2008;142(6):859-876.
Summary
Diamond Blackfan anemia (DBA) is a rare, genetically and clinically heterogeneous, inherited red cell aplasia. Classical DBA presents during the first year of life, affecting about 7 per million live births. However, as genes mutated in DBA have been discovered, non-classical cases with less distinct phenotypes are being described in adults as well as children. In caring for these patients it is often difficult to have a clear understanding of the treatment options and their outcomes because of the lack of complete information on the natural history of the disease. The purpose of this document is to review the criteria for diagnosis, evaluate the available treatment options, including corticosteroid and transfusion therapies and stem cell transplantation, and propose a plan for optimizing patient care. Congenital anomalies, mode of inheritance, cancer predisposition, and pregnancy in DBA are also reviewed. Evidence-based conclusions will be made when possible; however, as in many rare diseases, the data are often anecdotal and the recommendations are based upon the best judgment of experienced clinicians. The recommendations regarding the diagnosis and management described in this report are the result of deliberations and discussions at an international consensus conference.
doi:10.1111/j.1365-2141.2008.07269.x
PMCID: PMC2654478  PMID: 18671700
Diamond Blackfan anemia (DBA); bone marrow failure; cancer predisposition; genetics; treatment
8.  Frameshift mutation in p53 regulator RPL26 is associated with multiple physical abnormalities and a specific pre-rRNA processing defect in Diamond-Blackfan anemia 
Human Mutation  2012;33(7):1037-1044.
Diamond-Blackfan anemia (DBA) is an inherited form of pure red cell aplasia that usually presents in infancy or early childhood and is associated with congenital malformations in ~30-50% of patients. DBA has been associated with mutations in nine ribosomal protein (RP) genes in about 53% of patients. We completed a large scale screen of 79 RP genes by sequencing 16 RP genes (RPL3, RPL7, RPL8, RPL10, RPL14, RPL17, RPL19, RPL23A, RPL26, RPL27, RPL35, RPL36A, RPL39, RPS4X, RPS4Y1, and RPS21) in 96 DBA probands. We identified a de novo two-nucleotide deletion in RPL26 in one proband associated with multiple severe physical abnormalities. This mutation gives rise to a remarkable ribosome biogenesis defect that affects maturation of both the small and the large subunits. We also found a deletion in RPL19 and missense mutations in RPL3 and RPL23A, which may be variants of unknown significance. Together with RPL5, RPL11, and RPS7, RPL26 is the fourth ribosomal protein regulating p53 activity that is linked to DBA.
doi:10.1002/humu.22081
PMCID: PMC3370062  PMID: 22431104
Diamond-Blackfan anemia; ribosomal protein genes; RPL26; ribosome biogenesis
9.  Dysferlin and Other Non-Red Cell Proteins Accumulate in the Red Cell Membrane of Diamond-Blackfan Anemia Patients 
PLoS ONE  2014;9(1):e85504.
Diamond Blackfan Anemia (DBA) is a congenital anemia usually caused by diverse mutations in ribosomal proteins. Although the genetics of DBA are well characterized, the mechanisms that lead to macrocytic anemia remain unclear. We systematically analyzed the proteomes of red blood cell membranes from multiple DBA patients to determine whether abnormalities in protein translation or erythropoiesis contribute to the observed macrocytosis or alterations in the mature red blood cell membrane. In depth proteome analysis of red cell membranes enabled highly reproducible identification and quantitative comparisons of 1100 or more proteins. These comparisons revealed clear differences between red cell membrane proteomes in DBA patients and healthy controls that were consistent across DBA patients with different ribosomal gene mutations. Proteins exhibiting changes in abundance included those known to be increased in DBA such as fetal hemoglobin and a number of proteins not normally found in mature red cell membranes, including proteins involved in the major histocompatibility complex class I pathway. Most striking was the presence of dysferlin in the red blood cell membranes of DBA patients but absent in healthy controls. Immunoblot validation using red cell membranes isolated from additional DBA patients and healthy controls confirmed a distinct membrane protein signature specific to patients with DBA.
doi:10.1371/journal.pone.0085504
PMCID: PMC3891812  PMID: 24454878
10.  Diamond Blackfan Anemia: a Tertiary Care Center Experience 
Diamond Blackfan Anemia (DBA) is a rare hypoplastic anemia that presents in infancy with macrocytic anemia and reticulocytopenia. It is a ribosomopathy with autosomal dominant inheritance.
In our series of 10 patients with DBA, congenital malformations were observed in 50% of the cases. Age at symptom onset ranged from 0–12 months. Age at diagnosis ranged from 4 months to 96 months. Male: female ratio was 9:1. Response to prednisolone was observed in 4 out of the 10 patients (either during initial treatment or during re-challenge). Response to cyclosporine was found to be poor. Bone marrow transplantation was successful in attaining remission in one patient. Malignancies were not reported in any patient possibly due to a short follow up period.
doi:10.4084/MJHID.2013.039
PMCID: PMC3684352  PMID: 23795277
11.  A Case of Diamond Blackfan Anemia (DBA) with Mutation in Ribosomal Protein S19 
Diamond Blackfan Anemia (DBA) is a rare disorder which presents with anemia in early infancy. This disorder is genetically and clinically heterogeneous in nature. The inheritance is mainly autosomal dominant. Approximately 25% of the cases are associated with craniofacial anomalies and some cases may end up in malignancy. The diagnosis is made by blood investigations, and bone marrow studies in which red cell precursors are reduced or absent. Screening for the mutations including those encoding for ribosomal proteins in the patient and the family members confirms the diagnosis. Human Leukocyte Antigen (HLA) matched hemopoietic stem cell transplantation is the treatment of choice. In other cases, corticosteroids and cyclosporine A have been tried. The haemoglobin level is maintained with packed red cell transfusion. We are presenting here a female baby who had anemia at birth and was brought to us at the age of 2 months. The diagnosis of DBA was made since the patient presented with anemia and showed reticulocytopenia, gross reduction in Red Blood Cell (RBC) count, and reduction in red cell precursors in the bone marrow. Genetic screening revealed mutation in ribosomal protein S19 (RPS19) gene in both the infant and the father.
doi:10.7860/JCDR/2014/7018.3899
PMCID: PMC3939545  PMID: 24596764
Anemia; Mutations; Human Leukocyte Antigen
12.  Osteosarcoma Associated With Diamond-Blackfan Anaemia: A Case of a Child Receiving Growth Hormone Therapy 
Sarcoma  2004;8(1):47-49.
Purpose: Diamond–Blackfan anaemia (DBA) is a rare pure congenital red cell aplasia, usually presenting in infancy or early childhood. The literature suggests a predisposition to haemopoietic malignancy but in addition solid tumours have been reported, with five cases of osteosarcoma described.
Patient: A sixth case of a 12-year-old girl with DBA who developed an osteosarcoma of the distal femur is presented.
Results: She was treated with methotrexate followed by tumour excision and distal femoral replacement. The patient is currently alive with multiple pulmonary metastases.
Discussion: We discuss the association between the administration of growth hormone and future development of malignancy in patients with DBA.
doi:10.1080/13577140410001679266
PMCID: PMC2395602  PMID: 18521394
13.  Ribosomal protein S19 and S24 insufficiency cause distinct cell cycle defects in Diamond-Blackfan anemia 
Biochimica et biophysica acta  2009;1792(10):1036-1042.
Diamond-Blackfan anemia (DBA) is a severe congenital anemia characterized by a specific decrease of erythroid precursors. The disease is also associated with growth retardation, congenital malformations, a predisposition for malignant disease and heterozygous mutations in either of the ribosomal protein (RP) genes RPS7, RPS17, RPS19, RPS24, RPL5, RPL11 and RPL35a. We show herein that primary fibroblast from DBA patients with truncating mutations in RPS19 or in RPS24 have a marked reduction in proliferative capacity. Mutant fibroblasts are associated with extended cell cycles and normal levels of p53 when compared to w.t. cells. RPS19 mutant fibroblasts accumulate in the G1 phase, whereas the RPS24 mutant cells show an altered progression in the S phase resulting in reduced levels in the G2/M phase. RPS19 deficient cells exhibit reduced levels of Cyclin-E, CDK2 and retinoblastoma (Rb) protein supporting a cell cycle arrest in the G1 phase. In contrast, RPS24 deficient cells show increased levels of the cell cycle inhibitor p21 and a seemingly opposing increase in Cyclin-E, CDK4 and CDK6. In combination, our results show that RPS19 and RPS24 insufficient fibroblasts have an impaired growth caused by distinct blockages in the cell cycle. We suggest this proliferative constraint to be an important contributing mechanism for the complex extra-hematological features observed in DBA.
doi:10.1016/j.bbadis.2009.08.002
PMCID: PMC2759502  PMID: 19689926
RPS19; RPS24; Diamond-Blackfan Anemia; Proliferation; Cell cycle; Cell cycle regulation
14.  Diamond Blackfan Anemia Treatment: Past, Present, and Future 
Seminars in hematology  2011;48(2):117-123.
Despite significant improvements in our understanding of the pathophysiology of Diamond Blackfan anemia (DBA), there have been few advances in therapy. The cornerstones of treatment remain corticosteroids, chronic red cell transfusions, and hematopoietic stem cell transplantation, each of which is fraught with complications. In this article, we will review the history of therapies that have been offered to patients with DBA, summarize the current standard of care including management of side effects, and discuss novel therapeutics that are being developed in the context of the research into the roles of ribosomal haploinsufficiency and p53 activation in Diamond Blackfan anemia.
doi:10.1053/j.seminhematol.2011.01.004
PMCID: PMC3073777  PMID: 21435508
15.  Oral and Dental Manifestations of Diamond-Blackfan Anemia: Case Reports 
European Journal of Dentistry  2011;5(3):344-348.
Diamond-Blackfan Anemia (DBA) is a red cell aplasia characterized with physical abnormalities. The incidence of the disease is reported to be five to seven (5–7) cases per million births in Europe and 4–5 per million live births in the UK and Netherlands with equal sex ratio. It was first recognized in 1938 but an exact pathophysiology of the disease has not been described yet. These abnormalities are well known, however, detailed oral and dental conditions related with the disease have not been described previously. We herein presented two cases of DBA together with oral and dental findings. Our study is first to report the gingival status of the patients with a complete investigation of any orthodontic or dental abnormalities in these kind of patients. A careful follow up and preventive therapies should not be missed in these kind of patients.
PMCID: PMC3137451  PMID: 21769279
Diamond-Blackfan Anemia; Dental; Periodontal; Oral
16.  Ribosomal protein mutations in Korean patients with Diamond-Blackfan anemia 
Diamond-Blackfan anemia (DBA) is a congenital bone marrow failure syndrome characterized by hypoproliferative anemia, associated physical malformations and a predisposition to cancer. DBA has been associated with mutations and deletions in the large and small ribosomal protein genes, and genetic aberrations have been detected in ∼50–60% of patients. In this study, nine Korean DBA patients were screened for mutations in eight known DBA genes (RPS19, RPS24, RPS17, RPS10, RPS26, RPL35A, RPL5 and RPL11) using the direct sequencing method. Mutations in RPS19, RPS26 and RPS17 were detected in four, two and one patient, respectively. Among the mutations detected in RPS19, two mutations were novel (c.26T>A, c.357-2A>G). For the mutation-negative cases, array-CGH analysis was performed to identify copy-number variations, and no deletions involving the known DBA gene regions were identified. The relative mRNA expression of RPS19 estimated using real-time quantitative PCR analysis revealed two- to fourfold reductions in RPS19 mRNA expression in three patients with RPS19 mutations, and p53 protein expression analysis by immunohistochemistry showed variable but significant nuclear staining in the DBA patients. In conclusion, heterozygous mutations in the known DBA genes RPS19, RPS26 and RPS17 were detected in seven out of nine Korean DBA patients. Among these patients, RPS19 was the most frequently mutated gene. In addition, decreased RPS19 mRNA expression and p53 overexpression were observed in the Korean DBA patients, which supports the hypothesis that haploinsufficiency and p53 hyperactivation represent a central pathway underlying the pathogenesis of DBA.
doi:10.1038/emm.2013.159
PMCID: PMC3972785  PMID: 24675553
array-CGH; Diamond-Blackfan anemia; ribosomal protein; sequencing
17.  Targeted Resequencing and Analysis of the Diamond-Blackfan Anemia Disease Locus RPS19 
PLoS ONE  2009;4(7):e6172.
Background
The Ribosomal protein S19 gene locus (RPS19) has been linked to two kinds of red cell aplasia, Diamond-Blackfan Anemia (DBA) and Transient Erythroblastopenia in Childhood (TEC). Mutations in RPS19 coding sequences have been found in 25% of DBA patients, but not in TEC patients. It has been suggested that non-coding RPS19 sequence variants contribute to the considerable clinical variability in red cell aplasia. We therefore aimed at identifying non-coding variations associated with DBA or TEC phenotypes.
Methodology/Principal Findings
We targeted a region of 19'980 bp encompassing the RPS19 gene in a cohort of 89 DBA and TEC patients for resequencing. We provide here a catalog of the considerable, previously unrecognized degree of variation in this region. We identified 73 variations (65 SNPs, 8 indels) that all are located outside of the RPS19 open reading frame, and of which 67.1% are classified as novel. We hypothesize that specific alleles in non-coding regions of RPS19 could alter the binding of regulatory proteins or transcription factors. Therefore, we carried out an extensive analysis to identify transcription factor binding sites (TFBS). A series of putative interaction sites coincide with detected variants. Sixteen of the corresponding transcription factors are of particular interest, as they are housekeeping genes or show a direct link to hematopoiesis, tumorigenesis or leukemia (e.g. GATA-1/2, PU.1, MZF-1).
Conclusions
Specific alleles at predicted TFBSs may alter the expression of RPS19, modify an important interaction between transcription factors with overlapping TFBS or remove an important stimulus for hematopoiesis. We suggest that the detected interactions are of importance for hematopoiesis and could provide new insights into individual response to treatment.
doi:10.1371/journal.pone.0006172
PMCID: PMC2703794  PMID: 19587786
18.  Hemin Augments Growth and Hemoglobinization of Erythroid Precursors from Patients with Diamond-Blackfan Anemia 
Anemia  2012;2012:940260.
Diamond-Blackfan anemia (DBA) is congenital pure red-cell anemia due to a differentiation block in erythroid precursors. The disease is commonly caused by mutations in genes for ribosomal proteins. Despite the identification of disease causal genes, the disease pathogenesis is not completely elucidated. The ribosomal abnormalities are assumed to inhibit globin translation which may lead to excess free heme, stimulating a generation of free radicals and thereby damaging the precursors. We studied the effect of hemin (heme chloride) on cultured human erythroid precursors and found that contrary to aforementioned hypothesis, although hemin moderately stimulated free radicals, it did not cause apoptosis or necrosis. In erythroid precursors derived from DBA patients, hemin significantly stimulated growth and hemoglobinization. Thus, heme toxicity is unlikely to play a role in the pathophysiology of most DBA cases. Moreover, its beneficial effect in culture suggests a therapeutic potential.
doi:10.1155/2012/940260
PMCID: PMC3359667  PMID: 22655180
19.  Exome sequencing identifies GATA1 mutations resulting in Diamond-Blackfan anemia  
The Journal of Clinical Investigation  2012;122(7):2439-2443.
Diamond-Blackfan anemia (DBA) is a hypoplastic anemia characterized by impaired production of red blood cells, with approximately half of all cases attributed to ribosomal protein gene mutations. We performed exome sequencing on two siblings who had no known pathogenic mutations for DBA and identified a mutation in the gene encoding the hematopoietic transcription factor GATA1. This mutation, which occurred at a splice site of the GATA1 gene, impaired production of the full-length form of the protein. We further identified an additional patient carrying a distinct mutation at the same splice site of the GATA1 gene. These findings provide insight into the pathogenesis of DBA, showing that the reduction in erythropoiesis associated with the disease can arise from causes other than defects in ribosomal protein genes. These results also illustrate the multifactorial role of GATA1 in human hematopoiesis.
doi:10.1172/JCI63597
PMCID: PMC3386831  PMID: 22706301
20.  OCULAR AND ORBITAL MANIFESTATIONS OF THE INHERITED BONE MARROW FAILURE SYNDROMES: FANCONI ANEMIA AND DYSKERATOSIS CONGENITA 
Ophthalmology  2009;117(3):615-622.
Purpose
The inherited bone marrow failure syndromes (IBMFS) are a heterogeneous group of genetic disorders that share the inability of the bone marrow to produce an adequate number of blood cells. The four most frequent syndromes are Fanconi anemia (FA), dyskeratosis congenita (DC), Diamond-Blackfan anemia (DBA) and Shwachman-Diamond syndrome (SDS). All four syndromes have been associated with various physical abnormalities. As part of a genotype/phenotype/cancer susceptibility study, we determined the prevalence of ophthalmic manifestations in these four syndromes.
Design
Cross-sectional study of a patient cohort.
Participants
Seventy-five patients with an IBMFS and 121 of their first degree relatives were seen in the National Eye Institute, National Institutes of Health from 2001 to 2007. The patient group included 22 FA, 28 DC, 19 DBA and six SDS.
Methods
Every participant underwent a complete ophthalmic evaluation, as well as digital facial photography with an adhesive paper ruler on the patient's forehead for an internal measure of scale. Interpupillary distance (IPD), inner canthal distance (ICD), outer canthal distance (OCD), palpebral fissure length (PFL) and corneal diameter (CD) were measured. Thirteen of the 22 patients with FA underwent axial length (AL) measurements by A-scan ultrasonography.
Main Outcome Measures
Type and prevalence of ophthalmic manifestations.
Results
Ninety-five percent of patients with FA had at least one abnormal parameter, and 25% at least four abnormal parameters. Eighty-two percent had small palpebral fissures, 69% simple microphthalmia, 64% small OCD, 55% microcornea, 28% ptosis, and six percent epicanthal folds. In patients with DC, abnormalities of the lacrimal drainage system (29%) were the most prevalent findings, followed by retinal abnormalities (pigmentary changes, retinal neovascularization, retinal detachment, exudative retinopathy) in 21%, cicatricial entropion with trichiasis and blepharitis in seven percent each, sparse eyelashes and congenital cataract in three and a half percent each. No significant ophthalmic abnormalities were seen in patients with DBA or SDS.
Conclusions
Syndrome-specific ocular findings are associated with FA and DC and may antedate diagnosis of the specific syndrome. Early recognition of these abnormalities is important for optimal management.
doi:10.1016/j.ophtha.2009.08.023
PMCID: PMC2830377  PMID: 20022637
21.  Diagnosing and treating Diamond Blackfan anaemia: results of an international clinical consensus conference 
British Journal of Haematology  2008;142(6):859-876.
Diamond Blackfan anaemia (DBA) is a rare, genetically and clinically heterogeneous, inherited red cell aplasia. Classical DBA affects about seven per million live births and presents during the first year of life. However, as mutated genes have been discovered in DBA, non-classical cases with less distinct phenotypes are being described in adults as well as children. In caring for these patients it is often difficult to have a clear understanding of the treatment options and their outcomes because of the lack of complete information on the natural history of the disease. The purpose of this document is to review the criteria for diagnosis, evaluate the available treatment options, including corticosteroid and transfusion therapies and stem cell transplantation, and propose a plan for optimizing patient care. Congenital anomalies, mode of inheritance, cancer predisposition, and pregnancy in DBA are also reviewed. Evidence-based conclusions will be made when possible; however, as in many rare diseases, the data are often anecdotal and the recommendations are based upon the best judgment of experienced clinicians. The recommendations regarding the diagnosis and management described in this report are the result of deliberations and discussions at an international consensus conference.
doi:10.1111/j.1365-2141.2008.07269.x
PMCID: PMC2654478  PMID: 18671700
Diamond Blackfan anaemia; bone marrow failure; cancer predisposition; genetics; treatment
22.  Diamond Blackfan anemia 2008 – 2009: Broadening the scope of ribosome biogenesis disorders 
Current opinion in pediatrics  2010;22(1):12-19.
Purpose of Review
Diamond Blackfan anemia (DBA) is an inherited bone marrow failure syndrome characterized by erythroid failure, congenital anomalies and predisposition to cancer. Recently, the notion of DBA as a disorder of ribosome biogenesis has been clarified. Correlations between molecular underpinnings and disease pathophysiology while elusive are beginning to emerge. Advances in these areas will be explored in this review
Recent Findings
All known genes mutated in DBA encode ribosomal proteins associated with either the small (RPS) or large (RPL) subunit and in these cases ribosomal protein haploinsufficiency gives rise to the disease. The number of genes affected, their potential interactions with the environment and modifier genes, and the myriad of potential signaling pathways linking abortive ribosome synthesis to cell cycle regulators may all contribute to disease heterogeneity. Genotype/phenotype relationships emerging over the past year promise to shed light on these complex interrelationships and their role in DBA pathophysiology.
Summary
The nosology of DBA has recently expanded to include two distinct disease categories; a classical inherited bone marrow failure syndrome and a “ribosomopathy”. The description of DBA as a ribosomopathy has provided a context for scientific inquiry analogous to the description of Fanconi anemia as a disorder of DNA repair.
doi:10.1097/MOP.0b013e328334573b
PMCID: PMC2886588  PMID: 19915471
Diamond Blackfan anemia (DBA); pure red cell aplasia; ribosome biogenesis; inherited bone marrow failure syndrome (IBMFS); cancer predisposition
23.  Diamond Blackfan Anemia: Diagnosis, Treatment and Molecular Pathogenesis 
Synopsis
Diamond Blackfan anemia (DBA) is a genetically and clinically heterogeneous disorder characterized by erythroid failure, congenital anomalies and a predisposition to cancer. Faulty ribosome biogenesis, resulting in pro-apoptotic erythropoiesis leading to erythroid failure, is hypothesized to be the underlying defect. The genes identified to date that are mutated in DBA all encode ribosomal proteins associated with either the small (RPS) or large (RPL) subunit and in these cases haploinsufficiency gives rise to the disease. Extraordinarily robust laboratory and clinical investigations have recently led to demonstrable improvements in clinical care for patients with DBA.
doi:10.1016/j.hoc.2009.01.004
PMCID: PMC2886591  PMID: 19327583
Diamond Blackfan anemia (DBA); pure red cell aplasia; ribosome biogenesis; inherited bone marrow failure syndrome (IBMFS); cancer predisposition
24.  What’s in a name? 
The Journal of Clinical Investigation  2012;122(7):2346-2349.
Mutations in numerous genes encoding ribosomal proteins (RPs) occur in 50%–70% of individuals with Diamond-Blackfan anemia (DBA), establishing the disease as a ribosomopathy. As described in this issue of JCI, Sankaran, Gazda, and colleagues used genome-wide exome sequencing to study DBA patients with no detectable mutations in RP genes. They identified two unrelated pedigrees in which the disease is associated with mutations in GATA1, which encodes an essential hematopoietic transcription factor with no known mechanistic links to ribosomes. These findings ignite an interesting and potentially emotional debate on how we define DBA and whether the term should be restricted to pure ribosomopathies. More generally, the work reflects the powerful knowledge and controversies arising from the deluge of data generated by new genetic technologies that are being used to analyze human diseases.
doi:10.1172/JCI63989
PMCID: PMC3386834  PMID: 22706300
25.  A microdeletion in 19q13.2 associated with mental retardation, skeletal malformations, and Diamond-Blackfan anaemia suggests a novel contiguous gene syndrome 
Journal of Medical Genetics  2000;37(2):128-131.
Diamond-Blackfan anaemia (DBA) is a constitutional red blood cell hypoplasia which may be associated with a variety of developmental abnormalities. A gene for DBA was recently mapped to chromosome 19q13.2 and subsequently cloned. Analysis of 19q marker alleles in DNA of sporadic DBA cases showed de novo microdeletions in three patients also presenting with mental retardation. We have studied one of these patients and characterised the deletion by fluorescence in situ hybridisation (FISH) to extended DNA fibres. The deletion was shown to be continuous over a 3.2 Mb region and the fibre-FISH analysis showed both chromosomal breakpoints. In combination, the clinical and molecular findings suggest a contiguous gene syndrome with a gene locus for mental retardation and, probably, skeletal malformations included in the deletion.


Keywords: chromosome 19q13; microdeletion syndrome; fibre-FISH
doi:10.1136/jmg.37.2.128
PMCID: PMC1734524  PMID: 10662814

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