Diamond-Blackfan anemia
| 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] Associate Editor(s)-in-Chief: Roghayeh Marandi[2]
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
Differentiating Diamond-Blackfan anemia from other Diseases
Epidemiology and Demographics
Risk Factors
Natural History, Complications and Prognosis
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[1]
- Eye problems such as cataracts, glaucoma, or strabismus
- kidney abnormalities
- hypospadias
- Secondary complications due to standard therapies( Corticosteroids treatment, Red cell transfusion, Bone marroe transplantation):
- Transfusion iron overload
- Cirrhosis or fibrosis of the liver
- Cardiac arrythmias
- Diabetes
- Reproductive organ failure
- Growth stunting
- Endocrine failure affecting the thyroid and adrenal
- Side effects of corticosteroids
- Osteoporosis
- Weight gain
- Cushingoid appearance
- Hypertension
- Diabetes mellitus
- Growth retardation
- Pathologic bone fractures
- Gastric ulcers
- Cataracts
- Glaucoma
- Increased susceptibility to infection
- Stem cell transplantation
- Graft vs. Host Disease (GVHD)
- Rejection
- Transfusion iron overload
Prognosis
- Prognosis is relatively good,Overall actuarial survival is 75% at age 40 years, 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. [2]
- 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.[3]
- Ultimately, 40% of case subjects remain dependent upon corticosteroids which increase the risk of heart disease, osteoporosis, and severe infections. [4]
- 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, and can cause severe co-morbidities.[5]
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.[6]
- 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
| Classical DBA
All diagnostic criteria are met
3 Diagnostic criteria + positive family history OR 2 Diagnostic criteria + 3 minor criteria OR 3 Minor criteria + positive family history
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. Hydrops fetalis in some cases have been seen.[7][8]
Symptoms
- Symptoms of anemia include pallor, irritability, failure to thrive, sleepiness, poor appetite, and weakness[9]
- Growth retardation (in about 30% )
- Congenital malformations, in particular craniofacial, upper-limb, heart, and genitourinary malformations:(~30%-50%):
Physical exam
Appearance of the Patient
- Pallor: primary hematologic feature is characterized by anemia (low red blood cell counts),usually develops during the neonatal period.
- Congenital malformations( observed in approximately 50% of affected individuals):
- Head and face (50%)
- Microcephaly
- hypertelorism
- Epicanthus
- Ptosis
- Microtia
- low-set ears
- Broad, depressed nasal bridge
- Cleft lip/palate
- High arched palate
- Micrognathia
- low anterior hairline
- Eye
- Congenital glaucoma
- Congenital cataract
- strabismus
- Neck
- Webbing, short neck,
- Klippel-Feil anomaly
- Sprengel deformity
- Upper limb and hand including thumb (38%)
- Absent radial artery
- Flat thenar eminence
- Triphalangeal, duplex, bifid, hypoplastic, or absent thumb
- Genitourinary (19%).
- Absent kidney
- horseshoe kidney
- hypospadias
- Heart (15%)
- Ventricular septal defect
- Atrial septal defect
- coarctation of the aorta
- Growth
- Low birth weight (in 25% of affected infants)
- Growth retardation9in 30%.Growth retardation can be influenced by other factors including steroid treatment
- Head and face (50%)
Following Initial Diagnosis, patients should be evaluated by:
- a hematologist
- a clinical geneticist for congenital malformations and to obtain a detailed family history
- an ophthalmologist for glaucoma and cataract for individuals on steroid therapy
- an Orthopedic evaluation for individuals with clinical findings suggestive of Klippel-Feil anomaly or Sprengel deformity
- Orthopedic for individuals with upper-limb and/or thumb anomalies
- Ultrasound examination of the kidney and urinary tract
- a nephrologist and a urologist, as appropriate
- a cardiologist including echocardiography
- Developmental assessment
Laboratory findings
Blood tests:
- Increased red-cell mean corpuscular volume (MCV)
- Reticulocytopenia
- Elevated erythrocyte adenosine deaminase activity(eADA)
- DBA is associated with an increased ADA activity 30– 33%. ADA 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.[10] [11]
- Elevated hemoglobin F (HbF) concentration
Genetic tests
1. A sequence analysis of RPS19 is performed first.
2. If no pathogenic variant in RPS19 is found, perform sequence analysis of the remaining pathologic variants which are known to cause DBA or other gene mutations.[12]
Bone marrow aspirate
- Normal marrow cellularity
- Erythroid hypoplasia
- Marked reduction in normoblasts
- Persistence of pronormoblasts on occasion
- Normal myeloid precursors and megakaryocytes[12]
Other tests
- Additional blood tests or genetic tests such as exome sequencing, genome sequencing, and mitochondrial sequencing may be ordered to rule out other types of anemia or other disorders.
- Diagnosis of related-therapies complications:
- Monitoring Transfusional Iron Overload with serum ferritin and Iron level. Here is a list of recommended labs to monitor and prevent the devastating effects of iron overload in the thyroid, heart, and the effects of diabetes:
- Total T3
- Total T4
- TSH
- T3 uptake (instead of free T4)
- IGF-1(monitors acute fluctuations in insulin action and determines inadequate insulin treatment or poor control of dietary intake)
- NT-proBNP (aids in the diagnosis of left ventricular dysfunction in heart failure)
- Antithyroid Abs (Antithyroglobulin and AntiThyroperoxidase)
- Fructosamine (useful in situations where the A1C cannot be reliably measured – as with transfused persons)
- Vitamin D
- Monitoring Transfusional Iron Overload with serum ferritin and Iron level. Here is a list of recommended labs to monitor and prevent the devastating effects of iron overload in the thyroid, heart, and the effects of diabetes:
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.[13] 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. [14]
- 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.[15]
- 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. Remission defined as an adequate Hemoglobin level without any treatment, lasting 6 months, independent of prior therapy. 72% of patients experience remission during the first decade of life. Some of them have more than one remission in their life. Relapses usually occur after a viral illness.
- Some patients who have such mild signs and symptoms do not require treatment.[3]
- 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
- 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
- Corticosteroids side effects:
- One of the critical side effects of corticosteroids is growth retardation. If growth is severely impaired, corticosteroids should be stopped.[12]
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 [6]
- Intravenous immunoglobulin
- High dose erythropoietin
- Interleukin-3
- Androgens
- Metoclopramide
- Leucine and lenalidomide
- Researchers still wants to know why steroids often work in DBA, find more mutations, and address some questions about Diamond-Blackfan anemia.[14]
Case Studies
External Links
- ↑ Luft F (January 2010). "The rise of a ribosomopathy and increased cancer risk". J. Mol. Med. 88 (1): 1–3. doi:10.1007/s00109-009-0570-0. PMID 20012593.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 6.0 6.1 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 anaemia: 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.
- ↑ 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.
- ↑ 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.
- ↑ Glader BE, Backer K (February 1988). "Elevated red cell adenosine deaminase activity: a marker of disordered erythropoiesis in Diamond-Blackfan anaemia and other haematologic diseases". Br. J. Haematol. 68 (2): 165–8. doi:10.1111/j.1365-2141.1988.tb06184.x. PMID 3348976.
- ↑ 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 (December 1998). "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)". Blood. 92 (11): 4422–7. PMID 9834249.
- ↑ 12.0 12.1 12.2 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) - ↑ 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.
- ↑ 14.0 14.1 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.