Diamond–Blackfan anemia
Diamond–Blackfan anemia is a congenital pure red blood cell aplasia that usually presents in infancy. DBA causes anemia, but has no effect on the other blood components. 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. There is a risk to develop acute myelogenous leukemia and certain other cancers.
A variety of other congenital abnormalities may also occur in DBA, such as triphalangeal thumbs, craniofacial abnormalities, and short stature.
Signs and symptoms
Diamond–Blackfan anemia is characterized by normocytic or macrocytic anemia with decreased erythroid progenitor cells 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.Genetics
Most pedigrees suggest an autosomal dominant mode of inheritance with incomplete penetrance. Approximately 10–25% of DBA occurs with a family history of disease.~70% of DBA cases can be attributed genetic mutations affecting ribosomal protein genes. The disease is characterized by genetic heterogeneity, affecting different ribosomal gene loci: Exceptions to this paradigm have been demonstrated, such as with rare mutations of transcription factor GATA1. RPS19, RPL5, RPS26, and RPL11 are the most frequently mutated genes in DBA patients. Given that ribosome function is essential for life, DBA patients carry loss-of-function alleles affecting only one copy. Initial descriptions of DBA patients primarily concentrated on nonsense and missense mutations within ribosomal protein coding sequences. However, recent findings suggest that extended splice site variations have not been sufficiently recognized and are quite common. Recent studies have begun to characterize the molecular signatures associated with specific mutations that lead to aberrant splicing impacting ribosomal proteins such as RPL11.
| name | chromosome | genotype | phenotype | protein | disruption |
| DBA1 | 19q13.2 | RPS19 | 30S to 18S | ||
| DBA2 | 8p23-p22 | unknown | |||
| DBA3 | 10q22-q23 | RPS24 | 30S to 18S | ||
| DBA4 | 15q | RPS17 | 30S to 18S | ||
| DBA5 | 3q29-qter | RPL35A | 32S to 5.8S/28S | ||
| DBA6 | 1p22.1 | RPL5 | 32S to 5.8S/28S | ||
| DBA7 | 1p36.1-p35 | RPL11 | 32S to 5.8S/28S | ||
| DBA8 | 2p25 | RPS7 | 30S to 18S | ||
| DBA9 | 6p | RPS10 | 30S to 18S | ||
| DBA10 | 12q | RPS26 | 30S to 18S | ||
| DBA11 | 17p13 | RPL26 | 30S to 18S | ||
| DBA12 | 3p24 | RPL15 | 45S to 32S | ||
| DBA13 | 14q | RPS29 | |||
| "other" | TSR2,RPS28, GATA1 SLC49A1 |
In 1997, a patient was identified who carried a rare balanced chromosomal translocation involving chromosome 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. Linkage 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 gene on chromosome 19 at cytogenetic position 19q13.2. Some previously undiagnosed relatives of DBA patients were found to carry mutations, and also had increased adenosine deaminase levels in their red blood cells, but had no other overt signs of disease.
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.
Malformations are seen more frequently with DBA6 RPL5 and DBA7 RPL11 mutations.
The genetic abnormalities underpinning the combination of DBA with Treacher Collins syndrome /mandibulofacial dysostosis phenotypes are heterogeneous, including RPS26, TSR2 which encodes a direct binding partner of RPS26, and RPS28.
Molecular basis
The phenotype of DBA patients suggests a hematological stem cell defect specifically affecting the erythroid progenitor population. Loss of ribosomal function might be predicted to affect translation and protein biosynthesis broadly and impact many tissues. However, DBA is characterized by dominant inheritance, and arises from partial loss of ribosomal function, so it is possible that erythroid progenitors are more sensitive to this decreased function, while most other tissues are less affected.Diagnosis
Typically, a diagnosis of DBA is made through a blood count and a bone marrow biopsy.A diagnosis of DBA is made on the basis of anemia, low reticulocyte 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.