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Diamond–Blackfan anemia

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Diamond–Blackfan anemia
Other namesBlackfan-Diamond anemia, inherited pure red cell aplasia,[1] inherited erythroblastopenia[2]
SpecialtyHematology

Diamond–Blackfan anemia (DBA) is a congenital erythroid aplasia that usually presents in infancy.[3] DBA causes low red blood cell counts (anemia), without substantially affecting the other blood components (the platelets and the white blood cells), which are usually 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. There is a risk to develop acute myelogenous leukemia (AML) and certain other cancers.[4]

A variety of other congenital abnormalities may also occur in DBA, such as hand anomalies.

Signs and symptoms

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Diamond–Blackfan anemia is characterized by normocytic or macrocytic anemia (low red blood cell counts) 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.[5] Low birth weight and generalized growth delay are sometimes observed. DBA patients have a modest risk of developing leukemia and other malignancies.[6]

Genetics

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Most pedigrees suggest an autosomal dominant mode of inheritance[1] with incomplete penetrance.[7] 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.[8] The disease is characterized by genetic heterogeneity, affecting different ribosomal gene loci:[9] Exceptions to this paradigm have been demonstrated, such as with rare mutations of transcription factor GATA1.[10][11] RPS19, RPL5, RPS26, and RPL11 are the most frequently mutated genes in DBA patients.[8] 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.[8] Recent studies have begun to characterize the molecular signatures associated with specific mutations that lead to aberrant splicing impacting ribosomal proteins such as RPL11.[12]

DBA types
name chromosome genotype[9] phenotype protein disruption
DBA1[9] 19q13.2 603474 105650 RPS19 30S to 18S[13]: 291 
DBA2 8p23-p22 unknown 606129
DBA3 10q22-q23 602412 610629 RPS24[14] 30S to 18S[13]: 291 
DBA4 15q 180472 612527 RPS17[15] 30S to 18S[13]: 291 
DBA5 3q29-qter 180468 612528 RPL35A[16] 32S to 5.8S/28S[13]: 291 
DBA6 1p22.1 603634 612561 RPL5[17] 32S to 5.8S/28S[13]: 291 
DBA7 1p36.1-p35 604175 612562 RPL11[17] 32S to 5.8S/28S[13]: 291 
DBA8 2p25 603658 612563 RPS7[17] 30S to 18S[13]: 291 
DBA9 6p 603632 613308 RPS10[9] 30S to 18S[18]
DBA10 12q 603701 613309 RPS26 30S to 18S[19]
DBA11 17p13 603704 614900 RPL26 30S to 18S[19]
DBA12 3p24 604174 615550 RPL15 45S to 32S[20]
DBA13 14q 603633 615909 RPS29
"other" TSR2,[21]RPS28,[21] GATA1

SLC49A1 (FLVCR1)

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.[citation needed]

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

Malformations are seen more frequently with DBA6 RPL5 and DBA7 RPL11 mutations.[7]

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.[21]

Molecular basis

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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.[citation needed]

Diagnosis

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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.[23]

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.[citation needed]About 20–25% of DBA patients may be identified with a genetic test for mutations in the RPS19 gene.

Treatment

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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.[24] 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, adverse events from BMTs may exceed those from iron overloading.[25] A 2007 one-subject study[26] showed the potential efficacy of leucine and isoleucine supplementation.

History

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First noted by Hugh W. Josephs in 1936,[1][27] the condition is however named for the pediatricians Louis K. Diamond and Kenneth Blackfan, who described congenital hypoplastic anemia in 1938.[28] Responsiveness to corticosteroids was reported in 1951.[1] In 1961, Diamond and colleagues presented longitudinal data on 30 patients and noted an association with skeletal abnormalities.[29] In 1997, a region on chromosome 19 was determined to carry a gene mutated in some DBA.[30][31] In 1999, mutations in the ribosomal protein S19 gene (RPS19) were found to be associated with disease in 42 of 172 DBA patients.[32] In 2001, a second DBA gene was localized to a region of chromosome 8, and further genetic heterogeneity was inferred.[33] Additional genes were subsequently identified.[9]

See also

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References

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  1. ^ a b c d 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" (PDF). Orpha.net. Retrieved 1 January 2010.
  3. ^ Pelagiadis I, et al. (2023). "The Diverse Genomic Landscape of Diamond–Blackfan Anemia: Two Novel Variants and a Mini-Review". Children. 10 (11): 1812. doi:10.3390/children10111812. PMC 10670567. PMID 38002903.
  4. ^ 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): 321–7. doi:10.1002/humu.20874. PMID 19191325.
  5. ^ Reference, Genetics Home. "Diamond-Blackfan anemia". Genetics Home Reference. Retrieved 2018-04-17.
  6. ^ "Diamond-Blackfan Anemia". Genetic and Rare Diseases Information Center. National Center for Advancing Translational Sciences. February 2023. Retrieved 12 June 2023.
  7. ^ a b Boria, I; Garelli, E; Gazda, H. T.; Aspesi, A; Quarello, P; Pavesi, E; Ferrante, D; Meerpohl, J. J.; Kartal, M; Da Costa, L; Proust, A; Leblanc, T; Simansour, M; Dahl, N; Fröjmark, A. S.; Pospisilova, D; Cmejla, R; Beggs, A. H.; Sheen, M. R.; Landowski, M; Buros, C. M.; Clinton, C. M.; Dobson, L. J.; Vlachos, A; Atsidaftos, E; Lipton, J. M.; Ellis, S. R.; Ramenghi, U; Dianzani, I (2010). "The ribosomal basis of Diamond-Blackfan Anemia: Mutation and database update". Human Mutation. 31 (12): 1269–79. doi:10.1002/humu.21383. PMC 4485435. PMID 20960466.
  8. ^ a b c Ulirsch, JC; Verboon, JM; Kazerounian, S; Guo, MH; Yuan, D; Ludwig, LS; Handsaker, RE; Abdulhay, NJ; Fiorini, C; Genovese, G; Lim, ET; Cheng, A; Cummings, BB; Chao, KR; Beggs, AH; Genetti, CA; Sieff, CA; Newburger, PE; Niewiadomska, E; Matysiak, M; Vlachos, A; Lipton, JM; Atsidaftos, E; Glader, B; Narla, A; Gleizes, PE; O'Donohue, MF; Montel-Lehry, N; Amor, DJ; McCarroll, SA; O'Donnell-Luria, AH; Gupta, N; Gabriel, SB; MacArthur, DG; Lander, ES; Lek, M; Da Costa, L; Nathan, DG; Korostelev, AA; Do, R; Sankaran, VG; Gazda, HT (6 December 2018). "The Genetic Landscape of Diamond-Blackfan Anemia". American Journal of Human Genetics. 103 (6): 930–947. doi:10.1016/j.ajhg.2018.10.027. PMC 6288280. PMID 30503522.
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  10. ^ Sankaran, Vijay G.; Ghazvinian, Roxanne; Do, Ron; Thiru, Prathapan; Vergilio, Jo-Anne; Beggs, Alan H.; Sieff, Colin A.; Orkin, Stuart H.; Nathan, David G. (2012-07-02). "Exome sequencing identifies GATA1 mutations resulting in Diamond-Blackfan anemia". Journal of Clinical Investigation. 122 (7): 2439–2443. doi:10.1172/jci63597. PMC 3386831. PMID 22706301.
  11. ^ Parrella, Sara; Aspesi, Anna; Quarello, Paola; Garelli, Emanuela; Pavesi, Elisa; Carando, Adriana; Nardi, Margherita; Ellis, Steven R.; Ramenghi, Ugo (2014-07-01). "Loss of GATA-1 full length as a cause of Diamond–Blackfan anemia phenotype". Pediatric Blood & Cancer. 61 (7): 1319–1321. doi:10.1002/pbc.24944. ISSN 1545-5017. PMC 4684094. PMID 24453067.
  12. ^ Panici, B; Nakajima, H; Carlston, CM; Ozadam, H; Cenik, C; Cenik, ES (July 2021). "Loss of coordinated expression between ribosomal and mitochondrial genes revealed by comprehensive characterization of a large family with a rare Mendelian disorder". Genomics. 113 (4): 1895–1905. doi:10.1016/j.ygeno.2021.04.020. PMC 8266734. PMID 33862179. S2CID 233277974.
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  14. ^ 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.
  15. ^ 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. S2CID 22482024.
  16. ^ 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.
  17. ^ a b c Gazda H. T.; Sheen M. R.; Vlachos A.; et al. (2008). "Ribosomal protein L5 and L11 mutations are associated with cleft palate and abnormal thumbs in Diamond-Blackfan anemia patients". The American Journal of Human Genetics. 83 (6): 769–80. doi:10.1016/j.ajhg.2008.11.004. PMC 2668101. PMID 19061985.
  18. ^ Online Mendelian Inheritance in Man (OMIM): 603632
  19. ^ a b Online Mendelian Inheritance in Man (OMIM): 603701
  20. ^ Online Mendelian Inheritance in Man (OMIM): 604174
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  22. ^ 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.
  23. ^ Williamson, MA; Snyder, LM. (2015). "Chapter 9". Wallach's Interpretation of Diagnostic Tests (10th ed.). Lippincott Williams & Wilkins. ISBN 9781451191769.
  24. ^ 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.
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  26. ^ 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): e66–7. doi:10.3324/haematol.11498. PMID 17562599.
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  28. ^ Diamond LK, Blackfan KD (1938). "Hypoplastic anemia". Am. J. Dis. Child. 56: 464–467.
  29. ^ Diamond LK, Allen DW, Magill FB (1961). "Congenital (erythroid) hypoplastic anemia: a 25 year study". Am. J. Dis. Child. 102 (3): 403–415. doi:10.1001/archpedi.1961.02080010405019. PMID 13722603.
  30. ^ 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. S2CID 6972423.
  31. ^ 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.
  32. ^ 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. S2CID 26664929.
  33. ^ 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.
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