|
|
| (29 intermediate revisions by the same user not shown) |
| Line 1: |
Line 1: |
| __NOTOC__ | | __NOTOC__ |
| | {{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}} {{AE}} [[User:Roghayeh Marandi|Roghayeh Marandi]][mailto:parastoo@aol.in] |
|
| |
|
| {{CMG}} {{AE}} [[User:Roghayeh Marandi|Roghayeh Marandi]][mailto:parastoo@aol.in] | | {{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 |
|
| |
|
| {{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 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.
| |
|
| |
|
| ==[[Diamond-Blackfan anemia historical perspective|Historical Perspective]]== | | ==[[Diamond-Blackfan anemia historical perspective|Historical Perspective]]== |
|
| |
| *Diamond and [[Kenneth Blackfan|Blackfan]] described congenital [[hypoplastic]] anemia in 1938.
| |
| *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.
| |
| *In 1997 a region on chromosome 19 was determined to carry a gene mutated in DBA.
| |
| *In 1999, mutations in the [[Ribosome|ribosomal]] protein S19 gene (RPS19) were found to be associated with disease in some of the patients.
| |
| *In 2001, it was determined that a second DBA gene lies in a region of chromosome 8.
| |
| *In 2007, Furthermore mutations in large ribosomal subunit-associated proteins rpl5, rpl11, and rpl35a, have been described.
| |
| *In 2010, 10 additional DBA genes are identified.
| |
| *Non-RP gene, GATA1, was identified in 2012.
| |
| *The largest study to date, "The Genetic Landscape of Diamond-Blackfan Anemia" provides a genetic explanation for nearly 80 percent of patients.
| |
| * 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]]== | | ==[[Diamond-Blackfan anemia pathophysiology|Pathophysiology]]== |
|
| |
|
| |
| Mutations in [[ribosomal]] protein genes have been confirmed to be the direct cause of faulty [[erythropoiesis]] and [[anemia]].. 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]]. 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. 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="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>
| |
|
| |
| 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.
| |
|
| |
|
| ==[[Diamond-Blackfan anemia causes|Causes]]== | | ==[[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. 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..Also, [[autosomal recessive]] inheritance, with a lesser frequency has been reported.Variable [[expressivity]] is seen in all RP gene mutations. Possible mechanisms underlying variable expressivity include an influence of modifier genes and environmental factors.
| |
| **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>
| |
| **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="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>[[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]]== | | ==[[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.
| |
| *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
| |
| *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]]== | | ==[[Diamond-Blackfan anemia epidemiology and demographics|Epidemiology and Demographics]]== |
|
| |
| *'''Incidence'''
| |
| Incidence of Classical Diamond-Blackfan anemia (DBA) is 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.
| |
|
| |
| *'''Prevalence of DBA'''
| |
| It is approximately 5000 cases worldwide.
| |
|
| |
| *'''Age'''
| |
| DBA is usually first diagnosed in infancy. The average age of presenting with anemia is two months and the average age of diagnosis with DBA is 3-4 months.
| |
| *Race
| |
| There is no racial predilection to DBA.
| |
| *'''Gender'''
| |
| DBA affects men and women equally.
| |
|
| |
|
| ==[[Diamond-Blackfan anemia risk factors|Risk Factors]]== | | ==[[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]]== | | ==[[Diamond-Blackfan anemia natural history, complications and prognosis|Natural History, Complications and Prognosis]]== |
|
| |
| '''Natural history'''
| |
|
| |
| 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]]).
| |
| **The symptomatic onset of Diamond black-fan anemia becomes apparent during the first year of life
| |
| *Approximately half of DBA cases have Congenital malformations, in particular [[craniofacial]], [[upper-limb]], heart, and [[genitourinar]]y 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
| |
| *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.
| |
| **Minimal or no evidence of congenital anomalies or short stature<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
| |
| *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
| |
|
| |
| ==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. <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.
| |
| *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, and can cause severe co-morbidities.
| |
|
| |
|
| ==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]] |
|
| |
| ==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. [[Hydrops fetalis]] in some cases have been seen.
| |
| '''Symptoms'''
| |
| *Symptoms of anemia include [[pallor]], [[irritability]], failure to thrive, sleepiness, 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 [[genitourinar]]y 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
| |
|
| |
|
| |
| 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.
| |
| *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.<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>
| |
|
| |
| '''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 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
| |
|
| |
|
| ==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]]
| |
| **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. 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.
| |
| *[[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.
| |
| '''[[Remission]]'''
| |
| *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.[https://doi.org/10.1182/blood.V112.11.3092.3092]
| |
| *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
| |
| *Corticosteroids side effects:
| |
| **One of the critical side effects of corticosteroids is growth retardation. If growth is severely impaired, corticosteroids should be stopped.<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>
| |
|
| |
| ==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]]
| |
|
| |
| * 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>
| |
|
| |
|
| ==Case Studies== | | ==Case Studies== |
| Line 345: |
Line 61: |
| [[Category:Hematology]] | | [[Category:Hematology]] |
| [[Category:Mature chapter]] | | [[Category:Mature chapter]] |
| <references />
| |