View source for Diamond-Blackfan anemia

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{{Infobox_Disease |
  Name           = {{PAGENAME}} |
  Image          = |
  Caption        = |
  DiseasesDB     = 29062 |
  ICD10          = {{ICD10|D|61|0|d|60}} |
  ICD9           = {{ICD9|284.01}} |
  ICDO           = |
  OMIM           = 105650 |
  MedlinePlus    = |
  MeshID         = D029503 |
}}
{{Diamond-Blackfan anemia}}

{{CMG}}

{{SK}} Erythrogenesis imperfecta; congenital pure red cell aplasia, hereditary pure red cell aplasia, familial pure red cell aplasia

==[[Diamond-Blackfan anemia overview|Overview]]==

'''Diamond-Blackfan anemia''' (DBA) is a [[congenital]] [[erythroid]] [[aplasia]] that usually presents in [[infancy]].The classic form is characterized by a profound normochromic and usually macrocytic anemia with normal leukocytes and platelets. About half of the affected patients have congenital malformations, and growth retardation in 30% of affected individuals. The symptoms and physical findings associated with DBA vary greatly from person to person.The hematologic complications occur in 90% of affected individuals during the first year of life.<ref name="pmid20301295">{{cite journal |vauthors=Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A |title= |journal= |volume= |issue= |pages= |date= |pmid=20301295 |doi= |url=}}</ref>

==[[Diamond-Blackfan anemia historical perspective|Historical Perspective]]==

*Diamond and [[Kenneth Blackfan|Blackfan]] described congenital [[hypoplastic]] anemia in 1938.<ref>{{cite journal | author=Diamond LK, Blackfan, KD | title=Hypoplastic anemia. | journal=Am. J. Dis. Child. | year=1938 | pages=464-467  | volume=56 }} </ref> 
*In 1951, responsiveness to corticosteroids was reported. 
*In 1961, Diamond and colleagues presented [[longitudinal]] data on 30 patients and noted an association with skeletal abnormalities. <ref>{{cite journal | author=Diamond LK, Allen DW, Magill FB | title= Congenital (erythroid) hypoplastic anemia: a 25 year study. | journal=Am. J. Dis. Child. | year=1961 | pages=403-415 | volume=102  | id=PMID 13722603}}
</ref> 
*In 1997 a region on chromosome 19 was determined to carry a gene mutated in DBA. <ref>{{cite journal | author= 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 | title= Diamond-Blackfan anaemia: genetic homogeneity for a gene on chromosome 19q13 restricted to 1.8 Mb. | journal=Nat. Genet. | year=1997 | pages=368-71 | volume=16 | issue=4  | id=PMID 9241274}}</ref><ref>{{cite journal | author= Gustavsson P, Skeppner G, Johansson B, Berg T, Gordon L, Kreuger A, Dahl N | title= Diamond-Blackfan anaemia in a girl with a de novo balanced reciprocal X;19 translocation. | journal=J. Med. Genet. | year=1997 | pages=779-82 | volume=34 | issue=9  | id=PMID 9321770}}</ref> 
*In 1999, mutations in the [[Ribosome|ribosomal]] protein S19 gene (RPS19) were found to be associated with disease in some of the patients.<ref>{{cite journal | author= 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 | title= The gene encoding ribosomal protein S19 is mutated in Diamond-Blackfan anaemia. | journal=Nat. Genet. | year=1999 | pages=168-75 | volume=21 | issue=2  | id=PMID 9988267}}</ref> 
*In 2001, it was determined that a second DBA gene lies in a region of chromosome 8.<ref>{{cite journal | author=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 | title= Evidence for linkage of familial Diamond-Blackfan anemia to chromosome 8p23.3-p22 and for non-19q non-8p disease. | journal=Blood | year=2001 | pages=2145-50 | volume=97 | issue=7  | id=PMID 11264183}}</ref>
*In 2007, Furthermore mutations in large ribosomal subunit-associated proteins rpl5, rpl11, and rpl35a, have been described. <ref name="pmid18535205">{{cite journal |vauthors=Farrar JE, Nater M, Caywood E, McDevitt MA, Kowalski J, Takemoto CM, Talbot CC, Meltzer P, Esposito D, Beggs AH, Schneider HE, Grabowska A, Ball SE, Niewiadomska E, Sieff CA, Vlachos A, Atsidaftos E, Ellis SR, Lipton JM, Gazda HT, Arceci RJ |title=Abnormalities of the large ribosomal subunit protein, Rpl35a, in Diamond-Blackfan anemia |journal=Blood |volume=112 |issue=5 |pages=1582–92 |date=September 2008 |pmid=18535205 |pmc=2518874 |doi=10.1182/blood-2008-02-140012 |url=}}</ref>
*In 2010, 10 additional DBA genes are identified.
*Non-RP gene, GATA1, was identified in 2012.<ref name="pmid24952648">{{cite journal |vauthors=Ludwig LS, Gazda HT, Eng JC, Eichhorn SW, Thiru P, Ghazvinian R, George TI, Gotlib JR, Beggs AH, Sieff CA, Lodish HF, Lander ES, Sankaran VG |title=Altered translation of GATA1 in Diamond-Blackfan anemia |journal=Nat. Med. |volume=20 |issue=7 |pages=748–53 |date=July 2014 |pmid=24952648 |pmc=4087046 |doi=10.1038/nm.3557 |url=}}</ref>
* Researchers still wants to know why steroids often work in DBA, find more mutations, and address some questions about Diamond-Blackfan anemia.<ref name="pmid30503522">{{cite journal |vauthors=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 |title=The Genetic Landscape of Diamond-Blackfan Anemia |journal=Am. J. Hum. Genet. |volume=103 |issue=6 |pages=930–947 |date=December 2018 |pmid=30503522 |pmc=6288280 |doi=10.1016/j.ajhg.2018.10.027 |url=}}</ref>

==[[Diamond-Blackfan anemia pathophysiology|Pathophysiology]]==
 

Mutations in [[ribosomal]] protein genes have been confirmed to be the direct cause of faulty [[erythropoiesis]] and [[anemia]].<ref name="pmid23463023">{{cite journal |vauthors=Vlachos A, Dahl N, Dianzani I, Lipton JM |title=Clinical utility gene card for Diamond-Blackfan anemia--update 2013 |journal=Eur. J. Hum. Genet. |volume=21 |issue=10 |pages= |date=October 2013 |pmid=23463023 |pmc=3778360 |doi=10.1038/ejhg.2013.34 |url=}}</ref>. DBA has revealed itself as a "Ribosomapthy".

{|class="wikitable"
|+
![[Ribosomal]] protein gene mutations---> [[Ribosomal]] protein Insufficiency ---> Imbalance of [[Ribosomal]] Assembly Intermediates ---> Free [[Ribosomal]] proteins bind to inhibitors of [[P53]] and Stabilize [[P53]] expression ---> [[P53]] Activation ---> [[Cell Cycle]] Arrest
|}

Researchers found [[Ribosomal]] protein gene mutations reduce the actual numbers of [[ribosomes]] in blood precursor cells. Without enough ribosomes, the precursors can’t produce enough [[GATA1]], which is essential for precursor cells to differentiate into [[red blood cells]], so mature red cells never form. Based on a documented pathogenetic hypothesis which has been named "''' ribosomal stress '''", ultimately a defective ribosome biosynthesis leads to [[apoptosis]] in those defective [[erythroid progenitors]] which in turn is leading to erythroid failure. In ‘‘ribosomal stress,  reduced RP synthesis activates [[p53]] that induces the downstream events and leads to cell cycle termination or [[apoptosis]].<ref name="pmid18641651">{{cite journal |vauthors=McGowan KA, Li JZ, Park CY, Beaudry V, Tabor HK, Sabnis AJ, Zhang W, Fuchs H, de Angelis MH, Myers RM, Attardi LD, Barsh GS |title=Ribosomal mutations cause p53-mediated dark skin and pleiotropic effects |journal=Nat. Genet. |volume=40 |issue=8 |pages=963–70 |date=August 2008 |pmid=18641651 |pmc=3979291 |doi=10.1038/ng.188 |url=}}</ref> Finally, this phenomenon results in the DBA phenotype of [[anemia]], deprived growth, and results in [[congenital]] abnormalities. Mutated RP genes in DBA encode [[ribosomal]] proteins which are involved in either the small (RPS) or large (RPL) subunits of these proteins and the scarcity of these proteins can result the development of the disease.<ref name="pmid19327583">{{cite journal |vauthors=Lipton JM, Ellis SR |title=Diamond-Blackfan anemia: diagnosis, treatment, and molecular pathogenesis |journal=Hematol. Oncol. Clin. North Am. |volume=23 |issue=2 |pages=261–82 |date=April 2009 |pmid=19327583 |pmc=2886591 |doi=10.1016/j.hoc.2009.01.004 |url=}}</ref> Other blood cells — like platelets, T cells, and B cells —  are not affected and can still develop since they’re not dependent on GATA1.<ref name="pmid28377399">{{cite journal |vauthors=O'Brien KA, Farrar JE, Vlachos A, Anderson SM, Tsujiura CA, Lichtenberg J, Blanc L, Atsidaftos E, Elkahloun A, An X, Ellis SR, Lipton JM, Bodine DM |title=Molecular convergence in ex vivo models of Diamond-Blackfan anemia |journal=Blood |volume=129 |issue=23 |pages=3111–3120 |date=June 2017 |pmid=28377399 |pmc=5465839 |doi=10.1182/blood-2017-01-760462 |url=}}</ref><ref name="pmid28615220">{{cite journal |vauthors=Ulirsch JC, Lareau C, Ludwig LS, Mohandas N, Nathan DG, Sankaran VG |title=Confounding in ex vivo models of Diamond-Blackfan anemia |journal=Blood |volume=130 |issue=9 |pages=1165–1168 |date=August 2017 |pmid=28615220 |pmc=5580274 |doi=10.1182/blood-2017-05-783191 |url=}}</ref><ref name="pmid24999938">{{cite journal |vauthors=Boultwood J, Pellagatti A |title=Reduced translation of GATA1 in Diamond-Blackfan anemia |journal=Nat. Med. |volume=20 |issue=7 |pages=703–4 |date=July 2014 |pmid=24999938 |doi=10.1038/nm.3630 |url=}}</ref><ref name="pmid24952648">{{cite journal |vauthors=Ludwig LS, Gazda HT, Eng JC, Eichhorn SW, Thiru P, Ghazvinian R, George TI, Gotlib JR, Beggs AH, Sieff CA, Lodish HF, Lander ES, Sankaran VG |title=Altered translation of GATA1 in Diamond-Blackfan anemia |journal=Nat. Med. |volume=20 |issue=7 |pages=748–53 |date=July 2014 |pmid=24952648 |pmc=4087046 |doi=10.1038/nm.3557 |url=}}</ref><ref name="pmid29551269">{{cite journal |vauthors=Khajuria RK, Munschauer M, Ulirsch JC, Fiorini C, Ludwig LS, McFarland SK, Abdulhay NJ, Specht H, Keshishian H, Mani DR, Jovanovic M, Ellis SR, Fulco CP, Engreitz JM, Schütz S, Lian J, Gripp KW, Weinberg OK, Pinkus GS, Gehrke L, Regev A, Lander ES, Gazda HT, Lee WY, Panse VG, Carr SA, Sankaran VG |title=Ribosome Levels Selectively Regulate Translation and Lineage Commitment in Human Hematopoiesis |journal=Cell |volume=173 |issue=1 |pages=90–103.e19 |date=March 2018 |pmid=29551269 |pmc=5866246 |doi=10.1016/j.cell.2018.02.036 |url=}}</ref> 

In the remaining 10-15% of DBA cases, no abnormal genes have yet been identified. It is likely that mutations are in a regulatory region including intronic regions and promoters in one of the known RP genes may account for the DBA phenotype. <ref name="pmid30228860">{{cite journal |vauthors=Da Costa L, Narla A, Mohandas N |title=An update on the pathogenesis and diagnosis of Diamond-Blackfan anemia |journal=F1000Res |volume=7 |issue= |pages= |date=2018 |pmid=30228860 |pmc=6117846 |doi=10.12688/f1000research.15542.1 |url=}}</ref>

==[[Diamond-Blackfan anemia causes|Causes]]==
*in about 80-85% of cases Diamond-Blackfan anemia, a block in [[erythropoiesis]] occurs due to the ribosomal protein gene mutation. <ref name="pmid30503522">{{cite journal |vauthors=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 |title=The Genetic Landscape of Diamond-Blackfan Anemia |journal=Am. J. Hum. Genet. |volume=103 |issue=6 |pages=930–947 |date=December 2018 |pmid=30503522 |pmc=6288280 |doi=10.1016/j.ajhg.2018.10.027 |url=}}</ref><ref name="pmid23463023">{{cite journal |vauthors=Vlachos A, Dahl N, Dianzani I, Lipton JM |title=Clinical utility gene card for: Diamond-Blackfan anemia--update 2013 |journal=Eur. J. Hum. Genet. |volume=21 |issue=10 |pages= |date=October 2013 |pmid=23463023 |pmc=3778360 |doi=10.1038/ejhg.2013.34 |url=}}</ref>

*In the remaining 10-15% of DBA cases, no abnormal genes have yet been identified. It is likely that mutations are in a regulatory region including intronic regions and promoters in one of the known RP genes and may account for the DBA phenotype. <ref name="pmid30228860">{{cite journal |vauthors=Da Costa L, Narla A, Mohandas N |title=An update on the pathogenesis and diagnosis of Diamond-Blackfan anemia |journal=F1000Res |volume=7 |issue= |pages= |date=2018 |pmid=30228860 |pmc=6117846 |doi=10.12688/f1000research.15542.1 |url=}}</ref>

*Ribosomal protein mutations are [[sprodaic]](55%) or [[hereditary]].
**Sporadic mutation occurs in genes encoding several different [[ribosomal]] proteins. 
**Approximately 40-45 % DBA cases are inherited with an [[autosomal dominant]] inheritance.<ref name="pmid22160079">{{cite journal |vauthors=Ball S |title=Diamond Blackfan anemia |journal=Hematology Am Soc Hematol Educ Program |volume=2011 |issue= |pages=487–91 |date=2011 |pmid=22160079 |doi=10.1182/asheducation-2011.1.487 |url=}}</ref><ref name="pmid23744582">{{cite journal |vauthors=Garçon L, Ge J, Manjunath SH, Mills JA, Apicella M, Parikh S, Sullivan LM, Podsakoff GM, Gadue P, French DL, Mason PJ, Bessler M, Weiss MJ |title=Ribosomal and hematopoietic defects in induced pluripotent stem cells derived from Diamond Blackfan anemia patients |journal=Blood |volume=122 |issue=6 |pages=912–21 |date=August 2013 |pmid=23744582 |pmc=3739037 |doi=10.1182/blood-2013-01-478321 |url=}}</ref> and they have a family history of the disease with varying phenotypes.<ref name="pmid30228860">{{cite journal |vauthors=Da Costa L, Narla A, Mohandas N |title=An update on the pathogenesis and diagnosis of Diamond-Blackfan anemia |journal=F1000Res |volume=7 |issue= |pages= |date=2018 |pmid=30228860 |pmc=6117846 |doi=10.12688/f1000research.15542.1 |url=}}</ref>, although some of cases (GATA1-related DBA and TSR2-related DBA) are inherited in an [[X-linked]] manner.<ref name="pmid20301769">{{cite journal |vauthors=Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, Clinton C, Gazda HT |title= |journal= |volume= |issue= |pages= |date= |pmid=20301769 |doi= |url=}}</ref>.Also, [[autosomal recessive]] inheritance, with a lesser frequency has been reported.<ref name="pmid30881276">{{cite journal |vauthors=Engidaye G, Melku M, Enawgaw B |title=Diamond Blackfan Anemia: Genetics, Pathogenesis, Diagnosis and Treatment |journal=EJIFCC |volume=30 |issue=1 |pages=67–81 |date=March 2019 |pmid=30881276 |pmc=6416817 |doi= |url=}}</ref>Variable [[expressivity]] is seen in all RP gene mutations. Possible mechanisms underlying variable expressivity include an influence of modifier genes and environmental factors. <ref name="pmid20960466">{{cite journal |vauthors=Boria I, Garelli E, Gazda HT, Aspesi A, Quarello P, Pavesi E, Ferrante D, Meerpohl JJ, Kartal M, Da Costa L, Proust A, Leblanc T, Simansour M, Dahl N, Fröjmark AS, Pospisilova D, Cmejla R, Beggs AH, Sheen MR, Landowski M, Buros CM, Clinton CM, Dobson LJ, Vlachos A, Atsidaftos E, Lipton JM, Ellis SR, Ramenghi U, Dianzani I |title=The ribosomal basis of Diamond-Blackfan Anemia: mutation and database update |journal=Hum. Mutat. |volume=31 |issue=12 |pages=1269–79 |date=December 2010 |pmid=20960466 |pmc=4485435 |doi=10.1002/humu.21383 |url=}}</ref>
**About 25% of patients have mutations in the [[ribosomal|ribosome]] protein S19 (RPS19) gene on chromosome 19 at [[cytogenetic]] position 19q13.2. RPS19 has an important role in 18S [[rRNA]] maturation in yeast and in human cells. 
**Other mutated genes have been found in RPL5, RPL11, RPL35A, RPS7, RPS10, RPS17, RPS24, and RPS26, and rarely in RPL15, RPL17, RPL19, RPL26, RPL27, RPL31, RPS15A, RPS20, RPS27, RPS28, RPS29, that result in small or large [[ribosomal]] [[subunit]] synthesis deficiencies in human cells<ref name="pmid30228860">{{cite journal |vauthors=Da Costa L, Narla A, Mohandas N |title=An update on the pathogenesis and diagnosis of Diamond-Blackfan anemia |journal=F1000Res |volume=7 |issue= |pages= |date=2018 |pmid=30228860 |pmc=6117846 |doi=10.12688/f1000research.15542.1 |url=}}</ref> <ref name="pmid18230666">{{cite journal |vauthors=Choesmel V, Fribourg S, Aguissa-Touré AH, Pinaud N, Legrand P, Gazda HT, Gleizes PE |title=Mutation of ribosomal protein RPS24 in Diamond-Blackfan anemia results in a ribosome biogenesis disorder |journal=Hum. Mol. Genet. |volume=17 |issue=9 |pages=1253–63 |date=May 2008 |pmid=18230666 |doi=10.1093/hmg/ddn015 |url=}}</ref>
**Mutation of "Non-RP" genes such as [[TSR2]] and [[GATA1]], and EPO also were found.<ref name="pmid30228860">{{cite journal |vauthors=Da Costa L, Narla A, Mohandas N |title=An update on the pathogenesis and diagnosis of Diamond-Blackfan anemia |journal=F1000Res |volume=7 |issue= |pages= |date=2018 |pmid=30228860 |pmc=6117846 |doi=10.12688/f1000research.15542.1 |url=}}</ref><ref name="pmid22706301">{{cite journal |vauthors=Sankaran VG, Ghazvinian R, Do R, Thiru P, Vergilio JA, Beggs AH, Sieff CA, Orkin SH, Nathan DG, Lander ES, Gazda HT |title=Exome sequencing identifies GATA1 mutations resulting in Diamond-Blackfan anemia |journal=J. Clin. Invest. |volume=122 |issue=7 |pages=2439–43 |date=July 2012 |pmid=22706301 |pmc=3386831 |doi=10.1172/JCI63597 |url=}}</ref><ref name="pmid24766296">{{cite journal |vauthors=Klar J, Khalfallah A, Arzoo PS, Gazda HT, Dahl N |title=Recurrent GATA1 mutations in Diamond-Blackfan anaemia |journal=Br. J. Haematol. |volume=166 |issue=6 |pages=949–51 |date=September 2014 |pmid=24766296 |doi=10.1111/bjh.12919 |url=}}</ref><ref name="pmid29551269">{{cite journal |vauthors=Khajuria RK, Munschauer M, Ulirsch JC, Fiorini C, Ludwig LS, McFarland SK, Abdulhay NJ, Specht H, Keshishian H, Mani DR, Jovanovic M, Ellis SR, Fulco CP, Engreitz JM, Schütz S, Lian J, Gripp KW, Weinberg OK, Pinkus GS, Gehrke L, Regev A, Lander ES, Gazda HT, Lee WY, Panse VG, Carr SA, Sankaran VG |title=Ribosome Levels Selectively Regulate Translation and Lineage Commitment in Human Hematopoiesis |journal=Cell |volume=173 |issue=1 |pages=90–103.e19 |date=March 2018 |pmid=29551269 |pmc=5866246 |doi=10.1016/j.cell.2018.02.036 |url=}}</ref><ref name="pmid28283061">{{cite journal |vauthors=Kim AR, Ulirsch JC, Wilmes S, Unal E, Moraga I, Karakukcu M, Yuan D, Kazerounian S, Abdulhay NJ, King DS, Gupta N, Gabriel SB, Lander ES, Patiroglu T, Ozcan A, Ozdemir MA, Garcia KC, Piehler J, Gazda HT, Klein DE, Sankaran VG |title=Functional Selectivity in Cytokine Signaling Revealed Through a Pathogenic EPO Mutation |journal=Cell |volume=168 |issue=6 |pages=1053–1064.e15 |date=March 2017 |pmid=28283061 |pmc=5376096 |doi=10.1016/j.cell.2017.02.026 |url=}}</ref>[[TSR2]] plays a role in ribosome biogenesis since it is involved in the [[pre-rRNA]] processing and binds to RPS26. [[GATA1]] which is the major erythroid transcription factor as being essential for precursor cells to differentiate into red blood cells and plays a critical role in regulating normal [[erythroid]] differentiation by activating of other erythroid genes.

==[[Diamond-Blackfan anemia differential diagnosis|Differentiating Diamond-Blackfan anemia from other Diseases]]==
*[[Aplastic anemia]]
*[[Fanconi anemia]] is a bone marrow failure syndrome, present with pancytopenia, and physical abnormalities usually present within the first decade of life.
*Transient Erythroblastopenia of Childhood is anacquired anemia usually (over 80%) presents at one year of age, while DBA usually (90%) presents before one year of age.<ref name="pmid31424886">{{cite journal |vauthors=Gadhiya K, Budh DP |title= |journal= |volume= |issue= |pages= |date= |pmid=31424886 |doi= |url=}}</ref>
*Shwachman-Diamond syndrome (SDS) is a clinical syndrome characterized by exocrine pancreatic dysfunction with [[malabsorption]], single or multi-lineage [[cytopenia]], growth failure, bone abnormality, and susceptibility to myelodysplastic syndrome, and AML<ref name="pmid29167174">{{cite journal |vauthors=Alter BP |title=Inherited bone marrow failure syndromes: considerations pre- and posttransplant |journal=Blood |volume=130 |issue=21 |pages=2257–2264 |date=November 2017 |pmid=29167174 |pmc=5714231 |doi=10.1182/blood-2017-05-781799 |url=}}</ref><ref name="pmid12496757">{{cite journal |vauthors=Boocock GR, Morrison JA, Popovic M, Richards N, Ellis L, Durie PR, Rommens JM |title=Mutations in SBDS are associated with Shwachman-Diamond syndrome |journal=Nat. Genet. |volume=33 |issue=1 |pages=97–101 |date=January 2003 |pmid=12496757 |doi=10.1038/ng1062 |url=}}</ref>
*Pearson syndrome is an inherited mDNA mutation characterized by sideroblastic anemia of childhood, exocrine pancreatic failure, liver failure, renal tubular defects, and pancytopenia. Death generally occurs in infancy due to liver failure.
*Dyskeratosis congenita (DC) is an inheretied disorder with the classic triad of lacy reticular [[pigmentation]] of the upper chest and/or neck, dysplastic nails, and oral [[leukoplakia]]. These patients have an increased risk of MDS, BMF, or AML. <ref name="pmid29167174">{{cite journal |vauthors=Alter BP |title=Inherited bone marrow failure syndromes: considerations pre- and posttransplant |journal=Blood |volume=130 |issue=21 |pages=2257–2264 |date=November 2017 |pmid=29167174 |pmc=5714231 |doi=10.1182/blood-2017-05-781799 |url=}}</ref>
*Cartilage-hair hypoplasia (CHH)It is an [[autosomal recessive]] inherited disorder characterized by anemia, macrocytosis, defective [[T cell-mediated]] immune response, short tubular bone, and fine sparse blond hair.
*Congenital amegakaryocytic thrombocytopenia (CAMT) usually presents at birth or in infancy with severe [[thrombocytopenia]], [[petechiae]], and/or intracranial or intestinal mucosal bleeding. In childhood, these patients may develop pancytopenia, MDS, or leukemia.
*Infections: [[Parvovirus B19]], [[HIV]], [[Viral hepatitis]]
*Drugs and toxins (eg. [[antileptic drugs]], [[azathioprine]])<ref name="pmid20301769">{{cite journal |vauthors=Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, Clinton C, Gazda HT |title= |journal= |volume= |issue= |pages= |date= |pmid=20301769 |doi= |url=}}</ref>
*Immune-mediated disorders( eg [[Thymoma]], [[Myasthenia Gravis]], [[SLE]])

==[[Diamond-Blackfan anemia epidemiology and demographics|Epidemiology and Demographics]]==

*Classical Diamond-Blackfan anemia (DBA) affects about seven per million live births per year. Thus in the United States, with 4 million live births per year, each year approximately 25-35 new patients  will be diagnosed.<ref name="pmid18671700">{{cite journal |vauthors=Vlachos A, Ball S, Dahl N, Alter BP, Sheth S, Ramenghi U, Meerpohl J, Karlsson S, Liu JM, Leblanc T, Paley C, Kang EM, Leder EJ, Atsidaftos E, Shimamura A, Bessler M, Glader B, Lipton JM |title=Diagnosing and treating Diamond Blackfan anemia: results of an international clinical consensus conference |journal=Br. J. Haematol. |volume=142 |issue=6 |pages=859–76 |date=September 2008 |pmid=18671700 |pmc=2654478 |doi=10.1111/j.1365-2141.2008.07269.x |url=}}</ref>

==[[Diamond-Blackfan anemia risk factors|Risk Factors]]==

*Positive family history of DBA
*Have a known genetic cause 
*The cause cannot be detected, in some cases

==[[Diamond-Blackfan anemia natural history, complications and prognosis|Natural History, Complications and Prognosis]]==

==Natural history==
The symptomatic onset of Diamond black-fan anemia becomes apparent during the first year of life. Approximately half of DBA cases have physical abnormalities.

The severity of Diamond-Blackfan anemia may vary, even within the same family.
*'''Classic DBA:'''
**Symptoms of [[anemia]] include [[fatigue]], weakness, and an abnormally pale appearance ([[pallor]]).
**All diagnostic criteria are met.

*Non-classic DBA:'''
**presents with mild or absent [[anemia]] with only subtle indications of erythroid abnormalities such as macrocytosis, elevated [[ADA]], and/or elevated [[HbF]] concentration
**Have mild anemia beginning later in childhood or in adulthood, while others have some of the physical features but no bone marrow problems.
**Congenital anomalies or short stature consistent with DBA and minimal or no evidence of abnormal<ref name="pmid20301769">{{cite journal |vauthors=Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, Clinton C, Gazda HT |title= |journal= |volume= |issue= |pages= |date= |pmid=20301769 |doi= |url=}}</ref>

==Complications==

*Common complications of Diamond black-fan include:
*Physical abnormalities
*higher-than-average chance of developing myelodysplastic syndrome (MDS), acute myeloid leukemia (AML) bone cancer (osteosarcoma), colon cancer<ref name="pmid20012593">{{cite journal |vauthors=Luft F |title=The rise of a ribosomopathy and increased cancer risk |journal=J. Mol. Med. |volume=88 |issue=1 |pages=1–3 |date=January 2010 |pmid=20012593 |doi=10.1007/s00109-009-0570-0 |url=}}</ref>
*Eye problems such as cataracts, glaucoma, or strabismus
*kidney abnormalities
*hypospadias

==Prognosis==
*Prognosis is relatively good, but complications related to treatment may alter the quality of life of the affected individuals. Severe complications as a result of treatment or the development of cancer may reduce life expectancy. <ref name="pmid31424886">{{cite journal |vauthors=Gadhiya K, Budh DP |title= |journal= |volume= |issue= |pages= |date= |pmid=31424886 |doi= |url=}}</ref>
*Hematopoietic stem cell transplant (HSCT) is the sole curative option, but carries significant morbidity and is generally restricted to those with a matched related donor.<ref name="pmid16041310">{{cite journal |vauthors=Roy V, Pérez WS, Eapen M, Marsh JC, Pasquini M, Pasquini R, Mustafa MM, Bredeson CN |title=Bone marrow transplantation for diamond-blackfan anemia |journal=Biol. Blood Marrow Transplant. |volume=11 |issue=8 |pages=600–8 |date=August 2005 |pmid=16041310 |doi=10.1016/j.bbmt.2005.05.005 |url=}}</ref>
*Ultimately, 40% of case subjects remain dependent upon corticosteroids which increase the risk of heart disease, osteoporosis, and severe infections. <ref name="pmid20960466">{{cite journal |vauthors=Boria I, Garelli E, Gazda HT, Aspesi A, Quarello P, Pavesi E, Ferrante D, Meerpohl JJ, Kartal M, Da Costa L, Proust A, Leblanc T, Simansour M, Dahl N, Fröjmark AS, Pospisilova D, Cmejla R, Beggs AH, Sheen MR, Landowski M, Buros CM, Clinton CM, Dobson LJ, Vlachos A, Atsidaftos E, Lipton JM, Ellis SR, Ramenghi U, Dianzani I |title=The ribosomal basis of Diamond-Blackfan Anemia: mutation and database update |journal=Hum. Mutat. |volume=31 |issue=12 |pages=1269–79 |date=December 2010 |pmid=20960466 |pmc=4485435 |doi=10.1002/humu.21383 |url=}}</ref> 
*Another 40% become dependent upon red cell transfusions which require regular chelation to prevent iron overload and increases the risk of alloimmunization and transfusion reactions, both of which can be severe co-morbidities.<ref name="pmid23016900">{{cite journal |vauthors=Horos R, von Lindern M |title=Molecular mechanisms of pathology and treatment in Diamond Blackfan Anaemia |journal=Br. J. Haematol. |volume=159 |issue=5 |pages=514–27 |date=December 2012 |pmid=23016900 |doi=10.1111/bjh.12058 |url=}}</ref>

==Diagnosis==
[[Diamond-Blackfan anemia history and symptoms|History and Symptoms]] | [[Diamond-Blackfan anemia physical examination|Physical Examination]] | [[Diamond-Blackfan anemia laboratory findings|Laboratory Findings]] |  [[Diamond-Blackfan anemia electrocardiogram|Electrocardiogram]] | [[Diamond-Blackfan anemia chest x ray|Chest X Ray]] | [[Diamond-Blackfan anemia CT|CT]] | [[Diamond-Blackfan anemia MRI|MRI]] | [[Diamond-Blackfan anemia echocardiography or ultrasound|Echocardiography or Ultrasound]] | [[Diamond-Blackfan anemia other imaging findings|Other Imaging Findings]] | [[Diamond-Blackfan anemia other diagnostic studies|Other Diagnostic Studies]]

==Diagnosis==
*Diagnosing DBA is usually hard due to its partial phenotypes and the wide inconsistency of clinical expressions.the International Clinical Consensus Conference stated diagnostic and supporting criteria for the diagnosis of DBA.<ref name="pmid18671700">{{cite journal |vauthors=Vlachos A, Ball S, Dahl N, Alter BP, Sheth S, Ramenghi U, Meerpohl J, Karlsson S, Liu JM, Leblanc T, Paley C, Kang EM, Leder EJ, Atsidaftos E, Shimamura A, Bessler M, Glader B, Lipton JM |title=Diagnosing and treating Diamond Blackfan anaemia: results of an international clinical consensus conference |journal=Br. J. Haematol. |volume=142 |issue=6 |pages=859–76 |date=September 2008 |pmid=18671700 |pmc=2654478 |doi=10.1111/j.1365-2141.2008.07269.x |url=}}</ref>

*'''Diagnostic criteria'''
**Normochromic, often macrocytic anemia developing in the first year of life
**Profound reticulocytopenia
**Normocellular bone marrow with selective deficiency of erythroid precursors
**Normal or slightly reduced leukocyte count
**Normal or slightly increased platelet count
*'''Major supporting criteria'''
**Gene mutation described in ‘‘classical’’ DBA
**Positive family history
*'''Minor supporting criteria'''
**Elevated erythrocyte adenosine deaminase activity
**Congenital anomalies described in ‘‘classical’’ DBA
**Elevated HbF
**No evidence of another inherited bone marrow failure syndrome
__NOTOC__
<br />
{| class="wikitable"
|+
|'''Classical DBA'''

All diagnostic criteria are met


'''Probable DBA'''

3 Diagnostic criteria + positive family history

OR

2 Diagnostic criteria + 3 minor criteria

OR

3 Minor criteria + positive family history


'''Non-classical DBA'''

DBA associated gene mutation without sufficient diagnostic criteria 
|}

==History and symptoms==
'''History'''
*DBA typically presents in infancy, most commonly with pallor and lethargy, median age at presentation is 8 weeks, with a median age at diagnosis of 12 weeks. Hydrops fetalis in some cases
<ref name="pmid23349008">{{cite journal |vauthors=Da Costa L, Chanoz-Poulard G, Simansour M, French M, Bouvier R, Prieur F, Couque N, Delezoide AL, Leblanc T, Mohandas N, Touraine R |title=First de novo mutation in RPS19 gene as the cause of hydrops fetalis in Diamond-Blackfan anemia |journal=Am. J. Hematol. |volume=88 |issue=2 |pages=160 |date=February 2013 |pmid=23349008 |doi=10.1002/ajh.23366 |url=}}</ref>
<ref name="pmid29599205">{{cite journal |vauthors=Wlodarski MW, Da Costa L, O'Donohue MF, Gastou M, Karboul N, Montel-Lehry N, Hainmann I, Danda D, Szvetnik A, Pastor V, Paolini N, di Summa FM, Tamary H, Quider AA, Aspesi A, Houtkooper RH, Leblanc T, Niemeyer CM, Gleizes PE, MacInnes AW |title=Recurring mutations in RPL15 are linked to hydrops fetalis and treatment independence in Diamond-Blackfan anemia |journal=Haematologica |volume=103 |issue=6 |pages=949–958 |date=June 2018 |pmid=29599205 |pmc=6058779 |doi=10.3324/haematol.2017.177980 |url=}}</ref>
*Family history of DBA consistent with autosomal dominant inheritance
'''Symptoms'''
*Symptoms of anemia include  pallor, irritability, failure to thrive, sleepiness, irritability, poor appetite, and weakness<ref name="pmid30228860">{{cite journal |vauthors=Da Costa L, Narla A, Mohandas N |title=An update on the pathogenesis and diagnosis of Diamond-Blackfan anemia |journal=F1000Res |volume=7 |issue= |pages= |date=2018 |pmid=30228860 |pmc=6117846 |doi=10.12688/f1000research.15542.1 |url=}}</ref>
*Growth retardation (in about 30% )
*Congenital malformations, in particular craniofacial, upper-limb, heart, and genitourinary malformations:(observed in ~30%-50%): 
**microcephaly
**low frontal hairline
**wide-set eyes (hypertelorism)
**droopy eyelids (ptosis)
**broad, flat bridge of the nose
**small, low-set ears
**small lower jaw (micrognathia)
**cleft palate
**cleft lip
**short, webbed neck
**Smaller and higher shoulder blades than usual
**malformed or absent thumbs

==Laboratory findings==
'''Blood tests:'''
*Increased red-cell mean corpuscular volume (MCV)
*Reticulocytopenia
*Elevated erythrocyte adenosine deaminase activity 
**DBA is associated with an increased eADA activity 30– 33. eADA is a critical enzyme of the purine salvage pathway, which enables the deamination of adenosine in inosine and 2'-deoxyadenosine deamination in deoxyinosine. It is also increased in some leukemias, lymphomas, and immune system disorders.<ref name="pmid3348976">{{cite journal |vauthors=Glader BE, Backer K |title=Elevated red cell adenosine deaminase activity: a marker of disordered erythropoiesis in Diamond-Blackfan anaemia and other haematologic diseases |journal=Br. J. Haematol. |volume=68 |issue=2 |pages=165–8 |date=February 1988 |pmid=3348976 |doi=10.1111/j.1365-2141.1988.tb06184.x |url=}}</ref> <ref name="pmid9834249">{{cite journal |vauthors=Willig TN, Pérignon JL, Gustavsson P, Gane P, Draptchinskaya N, Testard H, Girot R, Debré M, Stéphan JL, Chenel C, Cartron JP, Dahl N, Tchernia G |title=High adenosine deaminase level among healthy probands of Diamond Blackfan anemia (DBA) cosegregates with the DBA gene region on chromosome 19q13. The DBA Working Group of Société d'Immunologie Pédiatrique (SHIP) |journal=Blood |volume=92 |issue=11 |pages=4422–7 |date=December 1998 |pmid=9834249 |doi= |url=}}</ref>
*Elevated hemoglobin F (HbF) concentration

'''Bone marrow aspirate'''
*Normal marrow cellularity
*Erythroid hypoplasia
*Marked reduction in normoblasts
*Persistence of pronormoblasts on occasion
*Normal myeloid precursors and megakaryocytes<ref name="pmid20301769">{{cite journal |vauthors=Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, Clinton C, Gazda HT |title= |journal= |volume= |issue= |pages= |date= |pmid=20301769 |doi= |url=}}</ref>

'''Other tests''' 
*Additional blood tests or genetic tests may be ordered to rule out other types of anemia or other disorders.

==Treatment==
[[Diamond-Blackfan anemia medical therapy|Medical Therapy]] | [[Diamond-Blackfan anemia surgery|Surgery]] | [[Diamond-Blackfan anemia cost-effectiveness of therapy|Cost-Effectiveness of Therapy]] | [[Diamond-Blackfan anemia future or investigational therapies|Future or Investigational Therapies]]
*[[Red cell transfusions]] 
**Transfusions are usually the mainstay of treatment for the first year of life for the anemia of DBA. Also, Red blood transfusions are used for those patients who do not respond to corticosteroid treatment
*[[Corticosteroid]] therapy
**after the first year patients are started on a course of treatment with corticosteroids and it remains the mainstay of treatment after the original report of their efficacy. In a large study of 225 patients, 82% initially responded to this therapy, although many side effects were noted.<ref>{{cite journal | author= Vlachos A, Klein GW, Lipton JM | title= The Diamond Blackfan Anemia Registry: tool for investigating the epidemiology and biology of Diamond-Blackfan anemia. | journal= J. Pediatr. Hematol. Oncol. | year=2001 | pages=377-82 | volume=23 | issue=6  | id=PMID 11563775}}</ref> Treatment with corticosteroids can improve the anemia in 80% of patients, but individuals often become intolerant to long-term corticosteroid therapy and turn to regular red blood cell transfusions, which is the only available standard therapy for the anemia. <ref name="pmid30503522">{{cite journal |vauthors=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 |title=The Genetic Landscape of Diamond-Blackfan Anemia |journal=Am. J. Hum. Genet. |volume=103 |issue=6 |pages=930–947 |date=December 2018 |pmid=30503522 |pmc=6288280 |doi=10.1016/j.ajhg.2018.10.027 |url=}}</ref>
**Chronic [[glucocorticoid]] therapy predisposes patients to iatrogenic Cushing syndrome and adrenal insufficiency. 
**Chronic [[blood transfusions]] place patients at risk for the iron overload of the liver, heart, and endocrine organs. Growth failure, osteopenia, diabetes mellitus, and failure of the thyroid, parathyroids, adrenals, gonads, and pituitary gland, may be related to therapy.<ref name="pmid26496000">{{cite journal |vauthors=Lahoti A, Harris YT, Speiser PW, Atsidaftos E, Lipton JM, Vlachos A |title=Endocrine Dysfunction in Diamond-Blackfan Anemia (DBA): A Report from the DBA Registry (DBAR) |journal=Pediatr Blood Cancer |volume=63 |issue=2 |pages=306–12 |date=February 2016 |pmid=26496000 |pmc=4829065 |doi=10.1002/pbc.25780 |url=}}</ref>
 
*[[Bone marrow transplantation]] (BMT)
**It is the only curative treatment for the anemia of DBA. This option may be considered when patients become transfusion-dependent because frequent transfusions can lead to iron overloading and organ damage. This can be done using an unaffected sibling or an unrelated donor.  
*Periods of [[remission]] may occur, during which transfusions and steroid treatments are not required.
*Some patients who have such mild signs and symptoms do not require treatment.
*Cancer treatment
*[[Prevention of secondary complications]]
*** Iron chelation
**** usually started after ten to 12 transfusions (170-200 mL/kg of packed red blood cells), when serum ferritin concentration reaches 1,000-1,500 µg/L, or when the hepatic iron concentration reaches 6-7 mg/g of dry weight liver tissue
***Deferasirox is recommended in individuals age two years or older.
***Desferrioxamine
*Evaluation of Relatives at Risk
**Molecular genetic testing if the pathogenic variant in the family is known
**Consideration of other testing (e.g., mean corpuscular volume, eADA, and/or fetal hemoglobin concentration) if the pathogenic variant in the family is not known – especially of relatives being considered as bone marrow donors

==Further or investigational therapies==
*Investigations of several other agents showed these drugs appear to be largely ineffective and there is currently no evidence that any of these has a major role in the management of DBA <ref name="pmid18671700">{{cite journal |vauthors=Vlachos A, Ball S, Dahl N, Alter BP, Sheth S, Ramenghi U, Meerpohl J, Karlsson S, Liu JM, Leblanc T, Paley C, Kang EM, Leder EJ, Atsidaftos E, Shimamura A, Bessler M, Glader B, Lipton JM |title=Diagnosing and treating Diamond Blackfan anaemia: results of an international clinical consensus conference |journal=Br. J. Haematol. |volume=142 |issue=6 |pages=859–76 |date=September 2008 |pmid=18671700 |pmc=2654478 |doi=10.1111/j.1365-2141.2008.07269.x |url=}}</ref>
**Intravenous immunoglobulin
**High dose erythropoietin
**Interleukin-3
**Androgens
**Metoclopramide
**Leucine and lenalidomide

==Case Studies==
[[Diamond-Blackfan anemia case study one|Case #1]]

==External Links==
* [http://dbafoundation.org/ Diamond Blackfan Anemia Foundation (USA)]

{{Hematology}}


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