Diamond-Blackfan anemia: Difference between revisions
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Revision as of 06:57, 6 August 2020
| Diamond-Blackfan anemia | |
| ICD-10 | D61.0 |
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| ICD-9 | 284.01 |
| OMIM | 105650 |
| DiseasesDB | 29062 |
| MeSH | D029503 |
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Diamond-Blackfan anemia Microchapters |
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Diagnosis |
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Treatment |
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Case Studies |
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Diamond-Blackfan anemia On the Web |
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American Roentgen Ray Society Images of Diamond-Blackfan anemia |
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Risk calculators and risk factors for Diamond-Blackfan anemia |
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Synonyms and keywords: Erythrogenesis imperfecta; congenital pure red cell aplasia, hereditary pure red cell aplasia, familial pure red cell aplasia
Overview
Historical Perspective
Pathophysiology
Causes
- A mutation in the RPS19 gene is the cause of DBA in about 25% of patients.
- 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.[1]
- Mutation in non-RP genes, TSR2, GATA1, and EPO.[1][2][3][4][5]
- Most often, Diamond-Blackfan anemia (DBA) is inherited in an autosomal dominant manner, although GATA1-related DBA and TSR2-related DBA are inherited in an X-linked manner.[6].Also,autosomal recessive inheritance, with a lesser frequency has been reported.[7]
- Variable expressivity is seen in all RP gene mutations. Possible mechanisms underlying variable expressivity include an influence of modifier genes and environmental factors. [8]
- 20 percent of patients still have no known genetic cause.[1]
Differentiating Diamond-Blackfan anemia from other Diseases
- Aplastic anemia
- Fanconi anemia
- Transient Erythroblastopenia of Childhood
- Shwachman-Diamond syndrome (SDS)[9][10]
- Pearson syndrome
- Dyskeratosis congenita (DC)[9]
- Cartilage-hair hypoplasia (CHH)
- Infections: Parvovirus B19, HIV, Viral hepatitis
- Drugs and toxins (eg. antileptic drugs, azathioprine)
- Immune-mediated disorders( eg Thymoma, Myasthenia Gravis, SLE)
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.[11]
- male-to-female ratio of cases is approximately 1:1 despite rare cases of X-linked inheritance
Risk Factors
Natural History, Complications and Prognosis
Natural history
Classic DBA:
- The symptomatic onset of Diamond black-fan anemia becomes apparent during the first year of life.
- Symptoms of anemia include fatigue, weakness, and an abnormally pale appearance (pallor).
- Approximately half of DBA cases have physical abnormalities.
- 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.
Non-classic DBA:
- presents with mild or absent anemia with only subtle indications of erythroid abnormalities such as macrocytosis, elevated eADA, and/or elevated HbF concentration
- Onset later in life
- Congenital anomalies or short stature consistent with DBA and minimal or no evidence of abnormal
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
- 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. [12]
- 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.[13]
- Ultimately, 40% of case subjects remain dependent upon corticosteroids which increase the risk of heart disease, osteoporosis, and severe infections. [8]
- 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.[14]
Diagnosis
History and Symptoms | Physical Examination | Laboratory Findings | Electrocardiogram | Chest X Ray | CT | MRI | Echocardiography or Ultrasound | Other Imaging Findings | 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.[11]
- 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
- The diagnosis is established when all four of the following diagnostic criteria are present:[11][15]
- Age younger than one year
- Macrocytic anemia with no other significant cytopenias
- Reticulocytopenia
- Normal marrow cellularity with a paucity of erythroid precursors
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
- 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[1]
- 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
Treatment
Medical Therapy | Surgery | Cost-Effectiveness of Therapy | 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.[18] 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. [19]
- 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.[20]
- 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
- Iron chelation
- 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 [11]
- Intravenous immunoglobulin
- High dose erythropoietin
- Interleukin-3
- Androgens
- Metoclopramide
- Leucine and lenalidomide
Case Studies
External Links
- ↑ 1.0 1.1 1.2 1.3 1.4 Da Costa L, Narla A, Mohandas N (2018). "An update on the pathogenesis and diagnosis of Diamond-Blackfan anemia". F1000Res. 7. doi:10.12688/f1000research.15542.1. PMC 6117846. PMID 30228860.
- ↑ Sankaran VG, Ghazvinian R, Do R, Thiru P, Vergilio JA, Beggs AH, Sieff CA, Orkin SH, Nathan DG, Lander ES, Gazda HT (July 2012). "Exome sequencing identifies GATA1 mutations resulting in Diamond-Blackfan anemia". J. Clin. Invest. 122 (7): 2439–43. doi:10.1172/JCI63597. PMC 3386831. PMID 22706301.
- ↑ Klar J, Khalfallah A, Arzoo PS, Gazda HT, Dahl N (September 2014). "Recurrent GATA1 mutations in Diamond-Blackfan anaemia". Br. J. Haematol. 166 (6): 949–51. doi:10.1111/bjh.12919. PMID 24766296.
- ↑ 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 (March 2018). "Ribosome Levels Selectively Regulate Translation and Lineage Commitment in Human Hematopoiesis". Cell. 173 (1): 90–103.e19. doi:10.1016/j.cell.2018.02.036. PMC 5866246. PMID 29551269.
- ↑ 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 (March 2017). "Functional Selectivity in Cytokine Signaling Revealed Through a Pathogenic EPO Mutation". Cell. 168 (6): 1053–1064.e15. doi:10.1016/j.cell.2017.02.026. PMC 5376096. PMID 28283061.
- ↑ 6.0 6.1 Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean L, Stephens K, Amemiya A, Clinton C, Gazda HT. PMID 20301769. Vancouver style error: initials (help); Missing or empty
|title=(help) - ↑ Engidaye G, Melku M, Enawgaw B (March 2019). "Diamond Blackfan Anemia: Genetics, Pathogenesis, Diagnosis and Treatment". EJIFCC. 30 (1): 67–81. PMC 6416817. PMID 30881276.
- ↑ 8.0 8.1 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 (December 2010). "The ribosomal basis of Diamond-Blackfan Anemia: mutation and database update". Hum. Mutat. 31 (12): 1269–79. doi:10.1002/humu.21383. PMC 4485435. PMID 20960466.
- ↑ 9.0 9.1 Alter BP (November 2017). "Inherited bone marrow failure syndromes: considerations pre- and posttransplant". Blood. 130 (21): 2257–2264. doi:10.1182/blood-2017-05-781799. PMC 5714231. PMID 29167174.
- ↑ Boocock GR, Morrison JA, Popovic M, Richards N, Ellis L, Durie PR, Rommens JM (January 2003). "Mutations in SBDS are associated with Shwachman-Diamond syndrome". Nat. Genet. 33 (1): 97–101. doi:10.1038/ng1062. PMID 12496757.
- ↑ 11.0 11.1 11.2 11.3 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 (September 2008). "Diagnosing and treating Diamond Blackfan anemia: results of an international clinical consensus conference". Br. J. Haematol. 142 (6): 859–76. doi:10.1111/j.1365-2141.2008.07269.x. PMC 2654478. PMID 18671700.
- ↑ Gadhiya K, Budh DP. PMID 31424886. Missing or empty
|title=(help) - ↑ Roy V, Pérez WS, Eapen M, Marsh JC, Pasquini M, Pasquini R, Mustafa MM, Bredeson CN (August 2005). "Bone marrow transplantation for diamond-blackfan anemia". Biol. Blood Marrow Transplant. 11 (8): 600–8. doi:10.1016/j.bbmt.2005.05.005. PMID 16041310.
- ↑ Horos R, von Lindern M (December 2012). "Molecular mechanisms of pathology and treatment in Diamond Blackfan Anaemia". Br. J. Haematol. 159 (5): 514–27. doi:10.1111/bjh.12058. PMID 23016900.
- ↑ Vlachos A, Muir E (November 2010). "How I treat Diamond-Blackfan anemia". Blood. 116 (19): 3715–23. doi:10.1182/blood-2010-02-251090. PMC 2981532. PMID 20651069.
- ↑ Da Costa L, Chanoz-Poulard G, Simansour M, French M, Bouvier R, Prieur F, Couque N, Delezoide AL, Leblanc T, Mohandas N, Touraine R (February 2013). "First de novo mutation in RPS19 gene as the cause of hydrops fetalis in Diamond-Blackfan anemia". Am. J. Hematol. 88 (2): 160. doi:10.1002/ajh.23366. PMID 23349008.
- ↑ 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 (June 2018). "Recurring mutations in RPL15 are linked to hydrops fetalis and treatment independence in Diamond-Blackfan anemia". Haematologica. 103 (6): 949–958. doi:10.3324/haematol.2017.177980. PMC 6058779. PMID 29599205.
- ↑ 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. PMID 11563775.
- ↑ 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 (December 2018). "The Genetic Landscape of Diamond-Blackfan Anemia". Am. J. Hum. Genet. 103 (6): 930–947. doi:10.1016/j.ajhg.2018.10.027. PMC 6288280. PMID 30503522.
- ↑ Lahoti A, Harris YT, Speiser PW, Atsidaftos E, Lipton JM, Vlachos A (February 2016). "Endocrine Dysfunction in Diamond-Blackfan Anemia (DBA): A Report from the DBA Registry (DBAR)". Pediatr Blood Cancer. 63 (2): 306–12. doi:10.1002/pbc.25780. PMC 4829065. PMID 26496000.