Diamond-Blackfan anemia
Encyclopedia
Diamond–Blackfan anemia (DBA), also known as Blackfan–Diamond anemia and Inherited erythroblastopenia, is a congenital erythroid aplasia
that usually presents in infancy. DBA patients have low red blood cell
counts (anemia
). The rest of their blood cells (the platelet
s and the white blood cell
s) are normal. This is in contrast to Shwachman–Bodian–Diamond syndrome
, in which the bone marrow
defect results primarily in neutropenia
, and Fanconi anemia
, where all cell lines are affected resulting in pancytopenia
.
A variety of other congenital abnormalities may also occur.
(low red blood cell
counts) with decreased erythroid progenitors in the bone marrow
. This usually develops during the neonatal period. About 47% of affected individuals also have a variety of congenital abnormalities, including craniofacial
malformations, thumb or upper limb abnormalities, cardiac defects, urogenital malformations, and cleft palate. Low birth weight and generalized growth delay are sometimes observed. DBA patients have a modest risk of developing leukemia
and other malignancies.
and a bone marrow biopsy
.
A diagnosis of DBA is made on the basis of anemia, low reticulocyte
(immature red blood cells) counts, and diminished erythroid precursors in bone marrow. Features that support a diagnosis of DBA include the presence of congenital abnormalities, macrocytosis
, elevated fetal hemoglobin
, and elevated adenosine deaminase
levels in red blood cells.
Most patients are diagnosed in the first two years of life. However, some mildly affected individuals only receive attention after a more severely affected family member is identified.
About 20–25% of DBA patients may be identified with a genetic test for mutations in the RPS19 gene.
and Blackfan
described congenital hypoplastic anemia in 1938. In 1961, Diamond and colleagues presented longitudinal
data on 30 patients and noted an association with skeletal abnormalities. In 1997 a region on chromosome 19 was determined to carry a gene mutated in DBA. In 1999, mutations in the ribosomal protein S19 gene (RPS19) were found to be associated with disease in 42 of 172 DBA patients. In 2001, it was determined that a second DBA gene lies in a region of chromosome 8 although evidence for further genetic heterogeneity was uncovered.
mutated in DBA.
Loci include:
stem cell
defect specifically affecting the erythroid progenitor population. This is difficult to reconcile with the known function of the single known DBA gene. The RPS19 protein is involved in the production of ribosomes. As such, loss of RPS19 function would be predicted to affect translation
and protein biosynthesis
and have a much broader impact. Disease features may be related to the nature of RPS19 mutations. The disease is characterized by dominant inheritance, and therefore arises due to a partial loss of RPS19 protein function. It is possible that erythroid progenitors are acutely sensitized to this decreased function, while most other tissues are unaffected.
waned in others. Blood transfusions can also be used to treat severe anemia in DBA. Periods of remission may occur, during which transfusions and steroid treatments are not required. Bone marrow transplantation (BMT) can cure hematological aspects of DBA. This option may be considered when patients become transfusion-dependent because frequent transfusions can lead to iron overloading and organ damage. However, data from a large DBA patient registry indicated that adverse events
in transfusion-dependent patients were more frequently caused by BMTs than iron overloading.
An article published on Feb. 10, 2009 http://www.dailymail.co.uk/health/article-1139624/Boy-baffling-illness-rare-does-cured-PARENTS.html?ITO=1490 reported that an eight year old boy with a DBA-like disease has been successfully treated by supplementing his diet with the amino acid
s leucine
and isoleucine
. A 2007 study shows the efficacy of a similar treatment on a different patient. Larger studies are being conducted.
Aplasia
Aplasia is defined in general as "defective development or congenital absence of an organ or tissue." In the field of hematology, the term refers to "incomplete, retarded, or defective development, or cessation of the usual regenerative process."-Examples:*Acquired pure red cell aplasia*Aplasia...
that usually presents in infancy. DBA patients have low red blood cell
Red blood cell
Red blood cells are the most common type of blood cell and the vertebrate organism's principal means of delivering oxygen to the body tissues via the blood flow through the circulatory system...
counts (anemia
Anemia
Anemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin...
). The rest of their blood cells (the platelet
Platelet
Platelets, or thrombocytes , are small,irregularly shaped clear cell fragments , 2–3 µm in diameter, which are derived from fragmentation of precursor megakaryocytes. The average lifespan of a platelet is normally just 5 to 9 days...
s and the white blood cell
White blood cell
White blood cells, or leukocytes , are cells of the immune system involved in defending the body against both infectious disease and foreign materials. Five different and diverse types of leukocytes exist, but they are all produced and derived from a multipotent cell in the bone marrow known as a...
s) are normal. This is in contrast to Shwachman–Bodian–Diamond syndrome
Shwachman–Bodian–Diamond syndrome
Shwachman–Diamond syndrome is a rare congenital disorder characterized by exocrine pancreatic insufficiency, bone marrow dysfunction, skeletal abnormalities, and short stature. After cystic fibrosis , it is the second most common cause of exocrine pancreatic insufficiency in children.-Clinical...
, in which the bone marrow
Bone marrow
Bone marrow is the flexible tissue found in the interior of bones. In humans, bone marrow in large bones produces new blood cells. On average, bone marrow constitutes 4% of the total body mass of humans; in adults weighing 65 kg , bone marrow accounts for approximately 2.6 kg...
defect results primarily in neutropenia
Neutropenia
Neutropenia, from Latin prefix neutro- and Greek suffix -πενία , is a granulocyte disorder characterized by an abnormally low number of neutrophils, the most important type of white blood cell...
, and Fanconi anemia
Fanconi anemia
Fanconi anemia is a genetic disease with an incidence of 1 per 350,000 births, with a higher frequency in Ashkenazi Jews and Afrikaners in South Africa.FA is the result of a genetic defect in a cluster of proteins responsible for DNA repair...
, where all cell lines are affected resulting in pancytopenia
Pancytopenia
Pancytopenia is a medical condition in which there is a reduction in the number of red and white blood cells, as well as platelets.If only two parameters from the full blood count are low, the term bicytopenia can be used...
.
A variety of other congenital abnormalities may also occur.
Clinical features
Diamond–Blackfan anemia is characterized by anemiaAnemia
Anemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin...
(low red blood cell
Red blood cell
Red blood cells are the most common type of blood cell and the vertebrate organism's principal means of delivering oxygen to the body tissues via the blood flow through the circulatory system...
counts) with decreased erythroid progenitors in the bone marrow
Bone marrow
Bone marrow is the flexible tissue found in the interior of bones. In humans, bone marrow in large bones produces new blood cells. On average, bone marrow constitutes 4% of the total body mass of humans; in adults weighing 65 kg , bone marrow accounts for approximately 2.6 kg...
. This usually develops during the neonatal period. About 47% of affected individuals also have a variety of congenital abnormalities, including craniofacial
Craniofacial
Craniofacial may be used to describe certain congenital malformations, injuries, surgeons who subspecialize in this area, multi-disciplinary medical-surgical teams that treat and do research on disorders affecting this region, and organizations with interest in...
malformations, thumb or upper limb abnormalities, cardiac defects, urogenital malformations, and cleft palate. Low birth weight and generalized growth delay are sometimes observed. DBA patients have a modest risk of developing leukemia
Leukemia
Leukemia or leukaemia is a type of cancer of the blood or bone marrow characterized by an abnormal increase of immature white blood cells called "blasts". Leukemia is a broad term covering a spectrum of diseases...
and other malignancies.
Diagnosis
Typically, a diagnosis of DBA is made through a blood countBlood Count
"Blood Count" is a 1967 jazz composition by Billy Strayhorn. It was originally meant for a three-piece work Strayhorn was writing for Duke Ellington and initially titled "Blue Cloud". However, Strayhorn was hospitalized in 1967 due to cancer and finished the composition while in the hospital. He...
and a bone marrow biopsy
Bone marrow biopsy
Bone marrow examination refers to the pathologic analysis of samples of bone marrow obtained by bone marrow biopsy and bone marrow aspiration. Bone marrow examination is used in the diagnosis of a number of conditions, including leukemia, multiple myeloma, lymphoma, anemia, and pancytopenia...
.
A diagnosis of DBA is made on the basis of anemia, low reticulocyte
Reticulocyte
Reticulocytes are immature red blood cells, typically composing about 1% of the red cells in the human body.Reticulocytes develop and mature in the red bone marrow and then circulate for about a day in the blood stream before developing into mature red blood cells. Like mature red blood cells,...
(immature red blood cells) counts, and diminished erythroid precursors in bone marrow. Features that support a diagnosis of DBA include the presence of congenital abnormalities, macrocytosis
Macrocytosis
Macrocytosis is the enlargement of red blood cells with near-constant hemoglobin concentration, and is defined by a mean corpuscular volume of greater than 100 femtolitres .- Causes :...
, elevated fetal hemoglobin
Fetal hemoglobin
Fetal hemoglobin, or foetal haemoglobin, is the main oxygen transport protein in the fetus during the last seven months of development in the uterus and in the newborn until roughly 6 months old...
, and elevated adenosine deaminase
Adenosine deaminase
Adenosine deaminase is an enzyme involved in purine metabolism. It is needed for the breakdown of adenosine from food and for the turnover of nucleic acids in tissues.-Reactions:...
levels in red blood cells.
Most patients are diagnosed in the first two years of life. However, some mildly affected individuals only receive attention after a more severely affected family member is identified.
About 20–25% of DBA patients may be identified with a genetic test for mutations in the RPS19 gene.
History
DiamondLouis K Diamond
Louis K. Diamond was an American pediatrician, known as the "father of pediatric hematology".Diamond was born in Kishinev, Bessarabia, at the time part of the Russian Empire. His family emigrated to the United States in 1904...
and Blackfan
Kenneth Blackfan
Kenneth Blackfan was an American pediatrician, born on September 9, 1883 in Cambridge, New York, and died November 1941.Blackfan began his medical studies at the Albany Medical School of Union University, New York, graduating at the age of only 22. Initially, he returned home to join his father in...
described congenital hypoplastic anemia in 1938. In 1961, Diamond and colleagues presented longitudinal
Longitudinal study
A longitudinal study is a correlational research study that involves repeated observations of the same variables over long periods of time — often many decades. It is a type of observational study. Longitudinal studies are often used in psychology to study developmental trends across the...
data on 30 patients and noted an association with skeletal abnormalities. In 1997 a region on chromosome 19 was determined to carry a gene mutated in DBA. In 1999, mutations in the ribosomal protein S19 gene (RPS19) were found to be associated with disease in 42 of 172 DBA patients. In 2001, it was determined that a second DBA gene lies in a region of chromosome 8 although evidence for further genetic heterogeneity was uncovered.
Genetics
Approximately 10–25% of DBA cases have a family history of disease, and most pedigrees suggest an autosomal dominant mode of inheritance. The disease is characterized by genetic heterogeneity, with current evidence supporting the existence of at least three genesGênes
Gênes is the name of a département of the First French Empire in present Italy, named after the city of Genoa. It was formed in 1805, when Napoleon Bonaparte occupied the Republic of Genoa. Its capital was Genoa, and it was divided in the arrondissements of Genoa, Bobbio, Novi Ligure, Tortona and...
mutated in DBA.
Loci include:
| Name/OMIM | Gene | Locus | Description |
|---|---|---|---|
| DBA1 | RPS19 | 19q13.2 | In 1997, a patient was identified who carried a rare balanced chromosomal translocation Chromosomal translocation In genetics, a chromosome translocation is a chromosome abnormality caused by rearrangement of parts between nonhomologous chromosomes. A gene fusion may be created when the translocation joins two otherwise separated genes, the occurrence of which is common in cancer. It is detected on... involving chromosome Chromosome A chromosome is an organized structure of DNA and protein found in cells. It is a single piece of coiled DNA containing many genes, regulatory elements and other nucleotide sequences. Chromosomes also contain DNA-bound proteins, which serve to package the DNA and control its functions.Chromosomes... 19 and the X chromosome. This suggested that the affected gene might lie in one of the two regions that were disrupted by this cytogenetic anomaly Congenital disorder A congenital disorder, or congenital disease, is a condition existing at birth and often before birth, or that develops during the first month of life , regardless of causation... . Linkage Genetic linkage Genetic linkage is the tendency of certain loci or alleles to be inherited together. Genetic loci that are physically close to one another on the same chromosome tend to stay together during meiosis, and are thus genetically linked.-Background:... analysis in affected families also implicated this region in disease, and led to the cloning of the first DBA gene. About 20–25% of DBA cases are caused by mutations in the ribosome protein S19 (RPS19) gene on chromosome 19 at cytogenetic position 19q13.2. Interestingly, some previously undiagnosed relatives of DBA patients were found to carry mutations. These patients also had increased adenosine deaminase levels in their red blood cells but no other overt signs of disease. |
| DBA2 | ? | 8p23-p22 | A subsequent study of families with no evidence of RPS19 mutations determined that 18 of 38 families showed evidence for involvement of an unknown gene on chromosome 8 at 8p23.3-8p22. The precise genetic defect in these families has not yet been delineated. |
| DBA3 | RPS24 RPS24 40S ribosomal protein S24 is a protein that in humans is encoded by the RPS24 gene.-Further reading:... |
10q22-q23 | |
| DBA4 | RPS17 RPS17 40S ribosomal protein S17 is a protein that in humans is encoded by the RPS17 gene.-External links:*... |
15q | |
| DBA5 | RPL35A RPL35A 60S ribosomal protein L35a is a protein that in humans is encoded by the RPL35A gene.-External links:*... |
3q29-qter | |
| DBA6 | RPL5 RPL5 60S ribosomal protein L5 is a protein that in humans is encoded by the RPL5 gene.- Function :Ribosomes, the organelles that catalyze protein synthesis, consist of a small 40S subunit and a large 60S subunit. Together these subunits are composed of 4 RNA species and approximately 80 structurally... |
1p22.1 | |
| DBA7 | RPL11 RPL11 60S ribosomal protein L11 is a protein that in humans is encoded by the RPL11 gene.-Interactions:RPL11 has been shown to interact with P16, BLMH, Mdm2, Promyelocytic leukemia protein and P53.-External links:*... |
1p36.1-p35 | |
| DBA8 | RPS7 RPS7 40S ribosomal protein S7 is a protein that in humans is encoded by the RPS7 gene.-Further reading:... |
2p25 |
Molecular basis of disease
The phenotype of DBA patients suggests a hematologicalHematology
Hematology, also spelled haematology , is the branch of biology physiology, internal medicine, pathology, clinical laboratory work, and pediatrics that is concerned with the study of blood, the blood-forming organs, and blood diseases...
stem cell
Stem cell
This article is about the cell type. For the medical therapy, see Stem Cell TreatmentsStem cells are biological cells found in all multicellular organisms, that can divide and differentiate into diverse specialized cell types and can self-renew to produce more stem cells...
defect specifically affecting the erythroid progenitor population. This is difficult to reconcile with the known function of the single known DBA gene. The RPS19 protein is involved in the production of ribosomes. As such, loss of RPS19 function would be predicted to affect translation
Translation (genetics)
In molecular biology and genetics, translation is the third stage of protein biosynthesis . In translation, messenger RNA produced by transcription is decoded by the ribosome to produce a specific amino acid chain, or polypeptide, that will later fold into an active protein...
and protein biosynthesis
Protein biosynthesis
Protein biosynthesis is the process in which cells build or manufacture proteins. The term is sometimes used to refer only to protein translation but more often it refers to a multi-step process, beginning with amino acid synthesis and transcription of nuclear DNA into messenger RNA, which is then...
and have a much broader impact. Disease features may be related to the nature of RPS19 mutations. The disease is characterized by dominant inheritance, and therefore arises due to a partial loss of RPS19 protein function. It is possible that erythroid progenitors are acutely sensitized to this decreased function, while most other tissues are unaffected.
Clinical management and treatments
Corticosteroids can be used to treat anemia in DBA. In a large study of 225 patients, 82% initially responded to this therapy, although many side effects were noted. Some patients remained responsive to steroids, while efficacyEfficacy
Efficacy is the capacity to produce an effect. It has different specific meanings in different fields. In medicine, it is the ability of an intervention or drug to reproduce a desired effect in expert hands and under ideal circumstances.- Healthcare :...
waned in others. Blood transfusions can also be used to treat severe anemia in DBA. Periods of remission may occur, during which transfusions and steroid treatments are not required. Bone marrow transplantation (BMT) can cure hematological aspects of DBA. This option may be considered when patients become transfusion-dependent because frequent transfusions can lead to iron overloading and organ damage. However, data from a large DBA patient registry indicated that adverse events
Adverse Events
"Adverse Events" is the third episode of the fifth season of House and the eighty-ninth episode overall. It first aired on September 30, 2008. Breckin Meyer guest starred as an artist who has an unexplained visual problem.- Plot :...
in transfusion-dependent patients were more frequently caused by BMTs than iron overloading.
An article published on Feb. 10, 2009 http://www.dailymail.co.uk/health/article-1139624/Boy-baffling-illness-rare-does-cured-PARENTS.html?ITO=1490 reported that an eight year old boy with a DBA-like disease has been successfully treated by supplementing his diet with the amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
s leucine
Leucine
Leucine is a branched-chain α-amino acid with the chemical formula HO2CCHCH2CH2. Leucine is classified as a hydrophobic amino acid due to its aliphatic isobutyl side chain. It is encoded by six codons and is a major component of the subunits in ferritin, astacin and other 'buffer' proteins...
and isoleucine
Isoleucine
Isoleucine is an α-amino acid with the chemical formula HO2CCHCHCH2CH3. It is an essential amino acid, which means that humans cannot synthesize it, so it must be ingested. Its codons are AUU, AUC and AUA....
. A 2007 study shows the efficacy of a similar treatment on a different patient. Larger studies are being conducted.
External Links
- Diamond Blackfan Anemia Foundation (USA)
- Daniella Maria Arturi Foundation Research For The Cure (USA)
- GeneReviews/NCBI/NIH/UW entry on Diamond–Blackfan Anemia
- OMIM entries on Diamond–Blackfan Anemia
- Diamond–Blackfan Anemia research study of Inherited Bone Marrow Failure Syndromes (IBMFS)
- UK Diamond Blackfan Anaemia Charity
- Diamond Blackfan Anæmia International Support Group
- Diamond Blackfan Anemia Registry of North America (DBAR)
- "'Designer baby' bid gets go-ahead" at BBC NewsBBC NewsBBC News is the department of the British Broadcasting Corporation responsible for the gathering and broadcasting of news and current affairs. The department is the world's largest broadcast news organisation and generates about 120 hours of radio and television output each day, as well as online...
, 4 May 2006 - Diamond Blackfan Anemia and You
- Diamond–Blackfan anemia Genetics Home Reference