Diamond–Blackfan anemia

Diamond–Blackfan anemia
Classification and external resources
Specialty hematology
ICD-10 D61.0
ICD-9-CM 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 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.

A variety of other congenital abnormalities may also occur in DBA.

Signs/symptoms

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. 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[1] with incomplete penetrance.[4] Approximately 10–25% of DBA occurs with a family history of disease.

With the exception of DBA rarely arising from mutation of transcription factor GATA1 [5][6] DBA arises from abnormal ribosomal protein genes.[1] The disease is characterized by genetic heterogeneity, affecting different ribosomal gene loci:[7]

DBA types
name chromosome genotype[7] phenotype protein disruption(cite)(cite)
DBA1[7] 19q13.2 603474 105650 RPS19 30S to 18S[8]:291(cite)
DBA2 8p23-p22 unknown 606129
DBA3 10q22-q23 602412 610629 RPS24[9] 30S to 18S[8]:291(cite)
DBA4 15q 180472 612527 RPS17[10] 30S to 18S[8]:291
DBA5 3q29-qter 180468 612528 RPL35A[11] 32S to 5.8S/28S[8]:291(cite)
DBA6 1p22.1 603634 612561 RPL5[12] 32S to 5.8S/28S[8]:291
DBA7 1p36.1-p35 604175 612562 RPL11[12] 32S to 5.8S/28S[8]:291
DBA8 2p25 603658 612563 RPS7[12] 30S to 18S[8]:291
DBA9 6p 603632 613308 RPS10[7] 30S to 18S[13]
DBA10 12q 603701 613309 RPS26 30S to 18S[14]
DBA11 17p13 603704 614900 RPS26 30S to 18S[14]
DBA12 3p24 604174 615550 RPL15 45S to 32S[15]
DBA13 14q 603633 615909 RPS29
"other" TSR2,[16]RPS28,[16] GATA1

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

Malformations are seen more frequently with DBA6 RPL5 and DBA7 RPL11 mutations.[4]

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.[16]


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 (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.[18]

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.

Treatment

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.[19] 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.[20]A 2007 study[21] showed the efficacy of leucine and isoleucine supplementation in one patient. Larger studies are being conducted.

History

First noted by Hugh W. Josephs in 1936,[1]:485[22] the condition is however named for the pediatricians Louis K. Diamond and Kenneth Blackfan, who described congenital hypoplastic anemia in 1938.[23] 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.[24] In 1997, a region on chromosome 19 was determined to carry a gene mutated in some DBA.[25][26] In 1999, mutations in the ribosomal protein S19 gene (RPS19) were found to be associated with disease in 42 of 172 DBA patients.[27] In 2001, a second DBA gene was localized to a region of chromosome 8, and further genetic heterogeneity was inferred.[28] Additional genes were subsequently identified.[7]

Notable cases

A girl named Audrey Nethery of Louisville, Kentucky has a large online following from her singing and dancing videos and has brought public attention to the very rare disease.[29][30] "The tiny dancer’s zest for the feel-happy, cool move packed, music pumping workout (Zumba) has inspired millions of people to fall in love with her. Subsequently, all the unexpected attention on Audrey has given her family a great opportunity to raise much needed awareness and funds for Diamond Blackfan Anemia (DBA)."[31] She's a big fan of American actress and singer Selena Gomez, who met Nethery and danced with her to a Gomez's song in a video that Gomez posted on her Instagram account; the video currently has over 19 million views. Nethery is also a big fan of American singer-songwriter Taylor Swift.

See also

References

  1. 1 2 3 4 5 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. ↑ 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. 1 2 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. PMID 20960466.
  5. ↑ 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.
  6. ↑ 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.
  7. 1 2 3 4 5 Online Mendelian Inheritance in Man. Diamond-Blackfan anemia. Johns Hopkins University.
  8. 1 2 3 4 5 6 7 Hoffbrand, AV; Moss PAH. (2011). Essential Haematology (6th ed.). Wiley-Blackwell. ISBN 978-1-4051-9890-5.
  9. ↑ 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 1698708Freely accessible. PMID 17186470.
  10. ↑ 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.
  11. ↑ 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 2518874Freely accessible. PMID 18535205.
  12. 1 2 3 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 2668101Freely accessible. PMID 19061985.
  13. ↑ Online Mendelian Inheritance in Man (OMIM) 603632
  14. 1 2 Online Mendelian Inheritance in Man (OMIM) 603701
  15. ↑ Online Mendelian Inheritance in Man (OMIM) 604174
  16. 1 2 3 Gripp K. W., Curry C, Olney A. H., Sandoval C, Fisher J, Chong J. X., UW , Genomics Mendelian, 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. 164A (9): 2240–9. doi:10.1002/ajmg.a.36633. PMC 4149220Freely accessible. PMID 24942156.
  17. ↑ 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.
  18. ↑ Williamson, MA; Snyder, LM. (2015). "Chapter 9". Wallach's Interpretation of Diagnostic Tests (10th ed.). Lippincott Williams & Wilkins. ISBN 9781451191769.
  19. ↑ 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.
  20. ↑ Saunders, E. F.; Olivieri, N; Freedman, M. H. (1993). "Unexpected complications after bone marrow transplantation in transfusion-dependent children". Bone marrow transplantation. 12 Suppl 1: 88–90. PMID 8374573.
  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.
  22. ↑ Hugh W. Josephs (1936). "Anaemia of infancy and early childhood". Medicine (Baltimore). 15: 307–451. doi:10.1097/00005792-193615030-00001.
  23. ↑ Diamond LK, Blackfan, KD (1938). "Hypoplastic anemia.". Am. J. Dis. Child. 56: 464–467.
  24. ↑ 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.
  25. ↑ 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.
  26. ↑ 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 1051068Freely accessible. PMID 9321770.
  27. ↑ 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.
  28. ↑ 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.
  29. ↑ https://www.youtube.com/channel/UCfCq-0GqaJQuZGcuGtnNgLQ
  30. ↑ http://www.womenyoushouldknow.net/6-year-old-audrey-nethery-puts-her-rare-blood-disorder-in-spotlight-with-awesome-zumba-moves-sets-sights-ellen-show/
  31. ↑ http://www.cosmopolitan.com/health-fitness/news/a45231/this-little-girl-is-better-at-zumba-than-youll-ever-be/
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