Diamond Blackfan disease
Diamond-Blackfan anemia (DBA) 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 platelets and the white blood cells) are normal. A variety of other congenital abnormalities may also occur. more...
Diamond-Blackfan anemia is characterized by anemia (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 retardation are sometimes observed. DBA patients have a modest risk of developing leukemia and other malignancies.
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.
Diamond and Blackfan described congenital hypoplastic anemia in 1938. In 1961, Diamond and colleagues presented longitudinal data on 30 patients and noted an associated 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.
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 genes mutated in DBA. 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 (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. 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. In a further 7 families, both the chromosome 19 and chromosome 8 loci could be excluded for involvement, suggesting the existence of at least one other DBA locus in the human genome.
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