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| {{Diamond-Blackfan anemia}} | | {{Diamond-Blackfan anemia}} |
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| {{CMG}}
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| {{SK}} Erythrogenesis imperfecta; congenital pure red cell aplasia, hereditary pure red cell aplasia, familial pure red cell aplasia | | {{CMG}} {{AE}} [[User:Roghayeh Marandi|Roghayeh Marandi]][mailto:parastoo@aol.in] |
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| | {{SK}} Erythrogenesis imperfecta; congenital pure red cell aplasia, hereditary pure red cell aplasia, familial pure red cell aplasia, RP: Ribosomal proteins, RPS: small ribosomal subunit, RPL: large ribosomal subunit, DBA: Diamond-Blackfan anemia, SDS: Shwachman-Diamond syndrome, AML: Acute myeloid leukemia, MDS: Myelodysplastic syndrome, BMF: Bone marrow failure, CHH: Cartilage-hair hypoplasia, CAMT: Congenital amegakaryocytic thrombocytopenia, HbF: Hemoglobin F |
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| ==[[Diamond-Blackfan anemia overview|Overview]]== | | ==[[Diamond-Blackfan anemia overview|Overview]]== |
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| ==[[Diamond-Blackfan anemia causes|Causes]]== | | ==[[Diamond-Blackfan anemia causes|Causes]]== |
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| *A mutation in the RPS19 gene is the cause of DBA in about 25% of patients.
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| *Mutations in RPL5, RPL11, RPL35A, RPS7, RPS10, RPS17, RPS24, and RPS26, and rarely in RPL15, RPL17, RPL19, RPL26, RPL27, RPL31, RPS15A, RPS20, RPS27, RPS28, RPS29 have also been 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>
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| *Mutation in non-RP genes, TSR2, GATA1, and EPO.<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>
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| * 20 percent of patients still have no known genetic cause.<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>
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| ==[[Diamond-Blackfan anemia differential diagnosis|Differentiating Diamond-Blackfan anemia from other Diseases]]== | | ==[[Diamond-Blackfan anemia differential diagnosis|Differentiating Diamond-Blackfan anemia from other Diseases]]== |
| *Aplastic anemia
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| *Fanconi anemia
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| *Transient Erythroblastopenia of Childhood
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| *Shwachman-Diamond syndrome (SDS)<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>
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| *Pearson syndrome
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| *Dyskeratosis congenita (DC)<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>
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| *Cartilage-hair hypoplasia (CHH)
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| *Infections: Parvovirus B19, HIV, Viral hepatitis
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| *Drugs and toxins (eg. antileptic drugs, azathioprine)
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| *Immune-mediated disorders( eg Thymoma, Myasthenia Gravis, SLE)
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| ==[[Diamond-Blackfan anemia epidemiology and demographics|Epidemiology and Demographics]]== | | ==[[Diamond-Blackfan anemia epidemiology and demographics|Epidemiology and Demographics]]== |
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| *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>
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| *male-to-female ratio of cases is approximately 1:1 despite rare cases of X-linked inheritance
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| <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>
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| ==[[Diamond-Blackfan anemia risk factors|Risk Factors]]== | | ==[[Diamond-Blackfan anemia risk factors|Risk Factors]]== |
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| ==[[Diamond-Blackfan anemia natural history, complications and prognosis|Natural History, Complications and Prognosis]]== | | ==[[Diamond-Blackfan anemia natural history, complications and prognosis|Natural History, Complications and Prognosis]]== |
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| ==Natural history==
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| Classic DBA:
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| *The symptomatic onset of Diamond black-fan anemia becomes apparent during the first year of life.
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| *Symptoms of anemia include fatigue, weakness, and an abnormally pale appearance (pallor).
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| *Approximately half of DBA cases have physical abnormalities.
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| *The severity of Diamond-Blackfan anemia may vary, even within the same family. individuals with "non-classical" Diamond-Blackfan anemia with less severe symptoms have been identified. For example, some affected individuals have mild anemia beginning later in childhood or in adulthood, while others have some of the physical features but no bone marrow problems.
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| Non-classic DBA:
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| *presents with mild or absent anemia with only subtle indications of erythroid abnormalities such as macrocytosis, elevated eADA, and/or elevated HbF concentration
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| *Onset later in life
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| *Congenital anomalies or short stature consistent with DBA and minimal or no evidence of abnormal
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| <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>
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| ==Complications==
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| *Common complications of Diamond black-fan include:
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| *Physical abnormalities
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| *higher-than-average chance of developing myelodysplastic syndrome (MDS), acute myeloid leukemia (AML) bone cancer (osteosarcoma), colon cancer
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| *Eye problems such as cataracts, glaucoma, or strabismus
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| *kidney abnormalities
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| *hypospadias
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| ==Prognosis==
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| *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>
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| *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>
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| *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>
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| ==Diagnosis== | | ==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]] | | [[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]] |
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| *The diagnosis is established when all four of the following diagnostic criteria are present:<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><ref name="pmid20651069">{{cite journal |vauthors=Vlachos A, Muir E |title=How I treat Diamond-Blackfan anemia |journal=Blood |volume=116 |issue=19 |pages=3715–23 |date=November 2010 |pmid=20651069 |pmc=2981532 |doi=10.1182/blood-2010-02-251090 |url=}}</ref>
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| **Age younger than one year
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| **Macrocytic anemia with no other significant cytopenias
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| **Reticulocytopenia
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| **Normal marrow cellularity with a paucity of erythroid precursors
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| ==History==
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| *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
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| <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>
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| <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>
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| *Family history of DBA consistent with autosomal dominant inheritance
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| ==symptoms==
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| *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>
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| *Growth retardation (in about 30% )
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| *Congenital malformations, in particular craniofacial, upper-limb, heart, and genitourinary malformations:(observed in ~30%-50%):
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| **microcephaly
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| **low frontal hairline
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| **wide-set eyes (hypertelorism)
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| **droopy eyelids (ptosis)
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| **broad, flat bridge of the nose
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| **small, low-set ears
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| **small lower jaw (micrognathia)
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| **cleft palate
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| **cleft lip
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| **short, webbed neck
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| **Smaller and higher shoulder blades than usual
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| **malformed or absent thumbs
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| ==Treatment== | | ==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]] | | [[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]]
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| **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
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| *[[Corticosteroid]] therapy
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| **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. Individuals with DBA, especially those on corticosteroid treatment, should take reasonable precautions to avoid infections
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| *[[Bone marrow transplantation]] (BMT)
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| **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.
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| *Periods of [[remission]] may occur, during which transfusions and steroid treatments are not required.
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| *Some patients who have such mild signs and symptoms do not require treatment.
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| *Cancer treatment
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| *[[Prevention of secondary complications]]
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| *** Iron chelation
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| **** 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
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| ***Deferasirox is recommended in individuals age two years or older.
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| ***Desferrioxamine
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| *Evaluation of Relatives at Risk
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| **Molecular genetic testing if the pathogenic variant in the family is known
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| **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
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| ==Further or investigational therapies==
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| *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>
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| **Intravenous immunoglobulin
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| **High dose erythropoietin
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| **Interleukin-3
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| **Androgens
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| **Metoclopramide
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| **Leucine and lenalidomide
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| ==Case Studies== | | ==Case Studies== |