Diamond–Blackfan anemia

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Diamond–Blackfan anemia
Classification and external resources
ICD-10 D61.0
ICD-9 284.01
OMIM 105650
DiseasesDB 29062
eMedicine article/205695-overview/
Patient UK Diamond–Blackfan anemia
MeSH D029503

Diamond-Blackfan anemia (DBA), also known as Blackfan-Diamond anemia, inherited pure red cell aplasia[1] and as inherited erythroblastopenia,[2] is a congenital erythroid aplasia that usually presents in infancy.[3] DBA causes low red blood cell counts (anemia), without affecting the other blood components (the platelets and the white blood cells), which 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.

Clinical features[edit]

Diamond–Blackfan anemia is characterized by macrocytic 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 delay are sometimes observed. DBA patients have a modest risk of developing leukemia and other malignancies.


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 (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.


First noted by Joseph in 1936,[1]:485[4] the condition is however named for Diamond and Blackfan, who described congenital hypoplastic anemia in 1938.[5] Responsiveness to corticosteroids was reported in 1951.[1]:485 In 1961, Diamond and colleagues presented longitudinal data on 30 patients and noted an association with skeletal abnormalities.[6] In 1997, a region on chromosome 19 was determined to carry a gene mutated in some DBA.[7][8] In 1999, mutations in the ribosomal protein S19 gene (RPS19) were found to be associated with disease in 42 of 172 DBA patients.[9] In 2001, a second DBA gene was localized to a region of chromosome 8, and further genetic heterogeneity was inferred.[10] Additional genes were subsequently identified.[11]


Most pedigrees suggest an autosomal dominant mode of inheritance.[1] Approximately 10–25% of DBA occurs with a family history of disease.

Diamond-Blackfan anemia arises from abnormal ribosomal protein genes.[1] The disease is characterized by genetic heterogeneity, affecting different ribosomal gene loci:[11]

Name OMIM phenotype[11] Protein OMIM genotype[11] Locus
DBA1 105650 RPS19 19q13.2
DBA2 606129  ? 8p23-p22
DBA3 610629 RPS24[12] 10q22-q23
DBA4 612527 RPS17[13] 15q
DBA5 612528 RPL35A[14] 3q29-qter
DBA6 612561 RPL5[15] 1p22.1
DBA7 612562 RPL11[15] 1p36.1-p35
DBA8 612563 RPS7[15] 2p25
DBA9 613308 RPS10[11] 6p
DBA10 613309 RPS26 603701 12q
DBA11 614900 RPS26 603704 17p13
DBA12 615550 RPL15 604174 3p24
DBA13 615909 RPS29 603633 14q

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. 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.[16] The precise genetic defect in these families has not yet been delineated.

Mutations in several ribosomal protein genes and the transcription factor GATA1 result in DBA

The genetic abnormalities underpinning the combination of DBA with Treacher Collins syndrome (TCS)/mandibulofacial dysostosis (MFD) phenotypes are heterogeneous, including RPS26 (the known DBA10 gene), TSR2 which encodes a direct binding partner of RPS26, and RPS28.[17]

Molecular basis of disease[edit]

The phenotype of DBA patients suggests a hematological 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.

Clinical management and treatments[edit]

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.[18] Some patients remained responsive to steroids, while efficacy 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, in part funded by both the Daniella Maria Arturi Foundation and the Diamond Blackfan Anemia Foundation, indicated that adverse events in transfusion-dependent patients were more frequently caused by BMTs than iron overloading.[19][20]

An article published on Feb. 10, 2009 [2] reported that an eight-year-old boy with a DBA-like disease has been successfully treated by supplementing his diet with the amino acids leucine and isoleucine. A 2007 study[21] shows the efficacy of a similar treatment on a different patient. Larger studies are being conducted.

See also[edit]


  1. ^ a b c d e Kaushansky, K; Lichtman, M; Beutler, E; Kipps, T; Prchal, J; Seligsohn, U. (2010). "35". Williams Hematology (8th ed.). McGraw-Hill. ISBN 978-0071621519. 
  2. ^ Tchernia, Gilbert; Delauney, J (June 2000). "Diamond–Blackfan anemia". Orpha.net. Retrieved 1 January 2010. 
  3. ^ Cmejla R, Cmejlova J, Handrkova H, et al. (February 2009). "Identification of mutations in the ribosomal protein L5 (RPL5) and ribosomal protein L11 (RPL11) genes in Czech patients with Diamond–Blackfan anemia". Hum. Mutat. 30 (3): n/a. doi:10.1002/humu.20874. PMID 19191325. 
  4. ^ Josephs HW (1936). "Anaemia of infancy and early childhood". Medicine (Baltimore) 15: 307–451. 
  5. ^ Diamond LK, Blackfan, KD (1938). "Hypoplastic anemia.". Am. J. Dis. Child. 56: 464–467. 
  6. ^ Diamond LK, Allen DW, Magill FB (1961). "Congenital (erythroid) hypoplastic anemia: a 25 year study.". Am. J. Dis. Child. 102: 403–415. doi:10.1001/archpedi.1961.02080010405019. PMID 13722603. 
  7. ^ Gustavsson P, Willing TN, van Haeringen A, Tchernia G, Dianzani I, Donner M, Elinder G, Henter JI, Nilsson PG, Gordon L, Skeppner G, van't Veer-Korthof L, Kreuger A, Dahl N (1997). "Diamond–Blackfan anaemia: genetic homogeneity for a gene on chromosome 19q13 restricted to 1.8 Mb.". Nat. Genet. 16 (4): 368–71. doi:10.1038/ng0897-368. PMID 9241274. 
  8. ^ Gustavsson P, Skeppner G, Johansson B, Berg T, Gordon L, Kreuger A, Dahl N (1997). "Diamond–Blackfan anaemia in a girl with a de novo balanced reciprocal X;19 translocation.". J. Med. Genet. 34 (9): 779–82. doi:10.1136/jmg.34.9.779. PMC 1051068. PMID 9321770. 
  9. ^ Draptchinskaia N, Gustavsson P, Andersson B, Pettersson M, Willig TN, Dianzani I, Ball S, Tchernia G, Klar J, Matsson H, Tentler D, Mohandas N, Carlsson B, Dahl N (1999). "The gene encoding ribosomal protein S19 is mutated in Diamond–Blackfan anaemia.". Nat. Genet. 21 (2): 168–75. doi:10.1038/5951. PMID 9988267. 
  10. ^ Gazda H, Lipton JM, Willig TN, Ball S, Niemeyer CM, Tchernia G, Mohandas N, Daly MJ, Ploszynska A, Orfali KA, Vlachos A, Glader BE, Rokicka-Milewska R, Ohara A, Baker D, Pospisilova D, Webber A, Viskochil DH, Nathan DG, Beggs AH, Sieff CA (2001). "Evidence for linkage of familial Diamond–Blackfan anemia to chromosome 8p23.3-p22 and for non-19q non-8p disease.". Blood 97 (7): 2145–50. doi:10.1182/blood.V97.7.2145. PMID 11264183. 
  11. ^ a b c d e Online Mendelian Inheritance in Man. Diamond-Blackfan anemia. Johns Hopkins University. [1]
  12. ^ Gazda HT, Grabowska A, Merida-Long LB, et al. (December 2006). "Ribosomal protein S24 gene is mutated in Diamond–Blackfan anemia". Am. J. Hum. Genet. 79 (6): 1110–8. doi:10.1086/510020. PMC 1698708. PMID 17186470. 
  13. ^ Cmejla R, Cmejlova J, Handrkova H, Petrak J, Pospisilova D (December 2007). "Ribosomal protein S17 gene (RPS17) is mutated in Diamond–Blackfan anemia". Hum. Mutat. 28 (12): 1178–82. doi:10.1002/humu.20608. PMID 17647292. 
  14. ^ Farrar JE, Nater M, Caywood E, et al. (September 2008). "Abnormalities of the large ribosomal subunit protein, Rpl35a, in Diamond–Blackfan anemia". Blood 112 (5): 1582–92. doi:10.1182/blood-2008-02-140012. PMC 2518874. PMID 18535205. 
  15. ^ a b c Gazda HT, Sheen MR, Vlachos A, et al. (December 2008). "Ribosomal protein L5 and L11 mutations are associated with cleft palate and abnormal thumbs in Diamond–Blackfan anemia patients". Am. J. Hum. Genet. 83 (6): 769–80. doi:10.1016/j.ajhg.2008.11.004. PMC 2668101. PMID 19061985. 
  16. ^ Gazda H, Lipton JM, Willig TN, et al. (April 2001). "Evidence for linkage of familial Diamond–Blackfan anemia to chromosome 8p23.3-p22 and for non-19q non-8p disease". Blood 97 (7): 2145–50. doi:10.1182/blood.V97.7.2145. PMID 11264183. 
  17. ^ Gripp, K. W.; Curry, C; Olney, A. H.; Sandoval, C; Fisher, J; Chong, J. X.; UW Center for Mendelian Genomics; Pilchman, L; Sahraoui, R; Stabley, D. L.; Sol-Church, K (2014). "Diamond-Blackfan anemia with mandibulofacial dystostosis is heterogeneous, including the novel DBA genes TSR2 and RPS28". American Journal of Medical Genetics Part A 164A (9): 2240–9.doi:10.1002/ajmg.a.36633. PMC 4149220. PMID 24942156
  18. ^ Vlachos A, Klein GW, Lipton JM (2001). "The Diamond Blackfan Anemia Registry: tool for investigating the epidemiology and biology of Diamond–Blackfan anemia.". J. Pediatr. Hematol. Oncol. 23 (6): 377–82. doi:10.1097/00043426-200108000-00015. PMID 11563775. 
  19. ^ "Daniella Maria Arturi Foundation: Funding". Retrieved 4 January 2013. 
  20. ^ "Diamond Blackfan Anemia Foundation: Funding". Retrieved 4 January 2013. 
  21. ^ Pospisilova D, Cmejlova J, Hak J, Adam T, Cmejla R (2007). "Successful treatment of a Diamond–Blackfan anemia patient with amino acid leucine.". Haematologica 92 (5): e66. doi:10.3324/haematol.11498. PMID 17562599. 

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