Diamond-Blackfan anemia

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Roghayeh Marandi
Synonyms and keywords: 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

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 and 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 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. The Non-RP gene, GATA1, was identified in 2012. Researchers still want to know why steroids often work in DBA, find more mutations, and address some questions about Diamond-Blackfan anemia.

The exact pathogenesis of DBA is “Ribosomapathy”. Mutations in ribosomal protein genes have been confirmed to be the direct cause of faulty erythropoiesis and anemia. Mutations reduce the actual numbers of ribosomes in blood precursor cells. Without enough ribosomes, the precursors can’t produce enough GATA1, so mature red cells never form. Other blood cells — like platelets, T cells, and B cells — are not affected since they’re not dependent on GATA1. Based on a documented pathogenetic hypothesis that 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, leading to erythroid failure.

Diamond-Blackfan anemia is caused by heterozygous mutation in a gene encoding a small (RPS7, RPS10, RPS15A, RPS17, RPS19, RPS20, RPS24, RPS26, RPS27, RPS28, RPS29) or large (RPL5, RPL11, RPL15, RPL17, RPL19, RPL26, RPL27, RPL31, RPL35A) ribosomal subunit-associated protein in 80%-85% of the affected cases of DBA. 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.

Diamond-Blackfan Anemia must be differentiated from other diseases that cause anemia and bone marrow failure such as Aplastic anemia, Fanconi anemia, Transient Erythroblastopenia of Childhood, Shwachman-Diamond syndrome, Pearson syndrome, Dyskeratosis congenita, Cartilage-hair hypoplasia, Congenital amegakaryocytic thrombocytopenia, Infections: Parvovirus B19, HIV, Viral hepatitis, Drugs, and toxins (eg. antileptic drugs, azathioprine), Immune-mediated disorders( eg Thymoma, Myasthenia Gravis, SLE).

The 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. The prevalence of DBA is approximately 5000 cases worldwide. 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. There is no racial predilection to DBA. DBA affects men and women equally.

Common risk factors in the development of DBA include positive family history, having a known genetic cause.

There is no routine screening.

DBA typically present with common symptoms of anemia, including pale skin, sleepiness, irritability, tachycardia. Common complications of DBA include physical abnormalities, Cancer predisposition, eye problems such as cataracts, glaucoma, or strabismus, kidney abnormalities, hypospadias, and secondary complications due to standard therapies( Corticosteroids treatment, Red cell transfusion, Bone marrow transplantation). Prognosis is relatively good, overall actuarial survival is 75% at age 40 years

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. Based on these criteria, there are two types of Diamond-Blackfan anemia, classical DBA and non-classical DBA. Classical DBA is made in the presence of all the diagnostic criteria and diagnosis of “non-classical DBA” in the presence of one of these criteria: i) Three diagnostic criteria and one major supporting criterion or two minor criteria; ii) Two diagnostic criteria, and three minor supporting criteria; iii) Two major supporting criteria, even in the absence of diagnostic criteria.

Patients with DBA may have a positive family history of DBA. The symptomatic onset of Diamond-Blackfan anemia becomes apparent during the first year of life. The most common symptoms of DBA include: fatigue, weakness, and an abnormally pale appearance (pallor). Approximately half of DBA cases have Congenital malformations, in particular craniofacial, upper-limb, heart, and genitourinary malformations.Patients with 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, and 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.

Common physical examination findings of DBA include signs of anemia such as pallor, tachycardia, and congenital abnormalities.

Laboratory findings consistent with the diagnosis of DBA include low reticulocyte counts and diminished erythroid precursors in the bone marrow. Blood tests, genetic tests, and bone marrow aspiration could help in the diagnosis of DBA.

There are no ECG findings associated with DBA. However, an ECG may be helpful in the diagnosis of related-therapies complications of DBA.

There are no chest x-ray findings associated with DBA. However, an x-ray may be helpful in the diagnosis of complications of DBA, which include related-therapies complications or congenital abnormalities.

Renal ultrasound and echocardiography should be done to diagnosis any renal or cardiac abnormalities.

There are no CT scan findings associated with DBA. It can use for the diagnosis of congenital physical abnormalities.

There are no MRI findings associated with DBA. It can use for the diagnosis of congenital physical abnormalities.

There are no other imaging findings associated with DBA.

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.other tests my be helpful in diagnosis of related-therapies complications such as iron overload.

Patients with DBA are treated with corticosteroid therapy, Red blood cell transfusion, Stem cell transplantation, Cancer treatment, and management of related-therapies complications. 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. 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.

Corrective surgery can be performed for the correction of congenital abnormalities.

Researchers still want to know why steroids often work in DBA, find more mutations, and address some questions about Diamond-Blackfan anemia.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Diamond and 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 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. The Non-RP gene, GATA1, was identified in 2012. Researchers still want to know why steroids often work in DBA, find more mutations, and address some questions about Diamond-Blackfan anemia.

• Diamond and Blackfan described congenital hypoplastic anemia in 1938.^[1]
• 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. ^[2]
• In 1997 a region on chromosome 19 was determined to carry a gene mutated in DBA. ^[3][4]
• In 1999, mutations in the ribosomal protein S19 gene (RPS19) were found to be associated with disease in some of the patients.^[5]
• In 2001, it was determined that a second DBA gene lies in a region of chromosome 8.^[6]
• In 2007, Furthermore mutations in large ribosomal subunit-associated proteins rpl5, rpl11, and rpl35a, have been described. ^[7]
• In 2010, 10 additional DBA genes are identified.
• Non-RP gene, GATA1, was identified in 2012.^[8]
• The largest study to date, “The Genetic Landscape of Diamond-Blackfan Anemia” provides a genetic explanation for nearly 80 percent of patients.”^[9]
• Researchers still wants to know why steroids often work in DBA, find more mutations, and address some questions about Diamond-Blackfan anemia.^[9]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Roghayeh Marandi
Keywords:RP: Ribosomal proteins, RPS: small ribosomal subunit, RPL: large ribosomal subunit, DBA: Diamond-Blackfan anemia

The exact pathogenesis of DBA is “Ribosomapathy”. Mutations in ribosomal protein genes have been confirmed to be the direct cause of faulty erythropoiesis and anemia. Mutations reduce the actual numbers of ribosomes in blood precursor cells. Without enough ribosomes, the precursors can’t produce enough GATA1, so mature red cells never form. Other blood cells — like platelets, T cells, and B cells — are not affected since they’re not dependent on GATA1. Based on a documented pathogenetic hypothesis that 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, leading to erythroid failure.

• The exact pathogenesis of DBA is “Ribosomapathy.”
• Mutations in ribosomal protein genes is the cause of faulty erythropoiesis and anemia.^[1].

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.^[2] 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 in the development of the disease.
• Non-Rp genes such as TSR2 and GATA1 also have an important role in the pathogenesis of DBA. 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.^[3]

• Other blood cells — like platelets, T cells, and B cells — are not affected and can still develop since they’re not dependent on GATA1.^{[4][5][6][7][8]}

• 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. ^[9]

Diamond-Blackfan anemia is caused by heterozygous mutation in a gene encoding a small (RPS7, RPS10, RPS15A, RPS17, RPS19, RPS20, RPS24, RPS26, RPS27, RPS28, RPS29) or large (RPL5, RPL11, RPL15, RPL17, RPL19, RPL26, RPL27, RPL31, RPL35A) ribosomal subunit-associated protein in 80%-85% of the affected cases of DBA. 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.

• In about 80-85% of cases Diamond-Blackfan anemia, a block in erythropoiesis occurs due to the ribosomal protein gene mutation. Ribosomal protein mutations are sprodaic(55%) or hereditary. Sporadic mutation occurs in genes encoding several different ribosomal proteins.

• About 25% of patients have mutations in the 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.

• Mutation of “Non-RP” genes such as TSR2 and GATA1, and EPO also were found.^{[1][2][3][4][5]}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. Approximately 40-45 % DBA cases are inherited with an autosomal dominant inheritance.^[6][7][8][9] and they have a family history of the disease with varying phenotypes.^[1], although some of cases (GATA1-related DBA and TSR2-related DBA) are inherited in an X-linked manner.^[10].Also, autosomal recessive inheritance, with a lesser frequency has been reported.^[11]Variable expressivity is seen in all RP gene mutations. Possible mechanisms underlying variable expressivity include an influence of modifier genes and environmental factors. Closing </ref> missing for <ref> tag ^[12]

• 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. ^[1]

Diamond-Blackfan Anemia must be differentiated from other diseases that cause anemia and bone marrow failure such as Aplastic anemia, Fanconi anemia, Transient Erythroblastopenia of Childhood, Shwachman-Diamond syndrome, Pearson syndrome, Dyskeratosis congenita, Cartilage-hair hypoplasia, Congenital amegakaryocytic thrombocytopenia, Infections: Parvovirus B19, HIV, Viral hepatitis, Drugs, and toxins (eg. antileptic drugs, azathioprine), Immune-mediated disorders( eg Thymoma, Myasthenia Gravis, SLE).

DBA should be differentiated from other bone marrow failure diseases and anemia.

• 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 an acquired anemia usually (over 80%) presents at one year of age, while DBA usually (90%) presents before one year of age.^[1]
• 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^[2][3]
• 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. ^[2]
• 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)^[4]
• Immune-mediated disorders( eg Thymoma, Myasthenia Gravis, SLE)

Disease	Genetics	Clinical manifestation					Lab findings
		History	Symptoms	Signs	Hemolysis	Intrinsic/ Extrinsic	Hb concentration	MCV	RDW	Reticulocytosis	Haptoglobin levels	Hepcidin	Iron studies					Specific finding on blood smear
													Serum iron	Serum Tfr level	Transferrin or TIBC	Ferritin	Transferrin saturation
Iron deficiency anemia[5]	−	Menorrhagia GI loss GI surgery Pregnancy	Koilonychia Pica	Glossitis Cheilosis Dysphagia	−	−	Hypochromic	Microcytic	↑	Nl or ↓	Nl	Nl	↓	↑	↑	↓	↓↓↓	Central pallor
Iron deficiency anemia (early phase)[6]	−	Pica Glossitis Cheilosis	Fatigue Headache	Koilonychia Conjunctival pallor Dry skin	−	−	Normochromic	Normocytic	↑	↓	Nl	Nl	↓	↑	↑	↓	↓	Pencil cells Elliptocytosis Hypochromasia
Lead poisoning[7]	−	House painted with chipped paint	Burtonian lines Basophilic stippling Wrist drop Foot drop	Wrist drop Foot drop Burtonian lines	−	−	Hypochromic	Microcytic	Nl	Nl or ↓	Nl	Nl	Nl to ↓	Nl	Nl	Nl to ↓	−	RBCs retain aggregates of rRNA Basophilic stippling
Sideroblastic anemia[8]	Defect in ALA synthase gene Autosomal dominant Autosomal recessive X-linked	Alcohol abuse Isoniazid use Chloramphenicol use Idiopathic	Seborrheic dermatitis Glossy Tongue Tingling	Patient present with symptoms of Vitamin B6, copper deficiency symptoms	−	−	Hypochromic	Microcytic	Nl	Nl or ↓	Nl	Nl	↑	Nl	Nl to ↓	↑	−	Ringed sideroblasts
Disease	Genetics	History	Symptoms	Signs	Hemolysis	Intrinsic/ Extrinsic	Hb concentration	MCV	RDW	Reticulocytosis	Haptoglobin levels	Hepcidin	Serum iron	Serum Tfr level	IBC	Ferritin	Transferrin saturation	Specific finding on blood smear
Anemia of chronic disease[9]	−	Rheumatoid arthritis SLE Neoplasm Chronic kidney disease	Headache Shortness of breath	−	−	−	Hypochromic	Microcytic	Nl	Nl or ↓	Nl	↑	↓	Nl	↓	↑	−	NA
Thalassemia[10]	α-thalassemia α– globin gene deletions Cis deletions Trans deletions β-thalassemia Point mutation in splice sites and promoter sequences	Associated with parvovirus B19	α-thalassemia Hydrops fetalis β-thalassemia Skeletal deformities Chipmunk facies	Hepatomegaly Splenomegaly	−	−	Hypochromic	Microcytic	Nl	Thalassemia trait: Nl or ↓ Thalassemia Syndromes: ↑	Nl	Nl	Nl to ↑	Nl	Nl	↑	Nl to ↑	Target cells Anisopoikilocytosis
G6pd deficiency[11]	Defect in G6PD enzyme X-Linked recessive	History of using Sulfa drugs Antimalarials Fava Beans Infections	Back pain Hemoglobinuria	Back pain	+	Intrinsic	Normochromic	Normocytic	↑	↑ but usually causes resolution within 4-7 days	↓	↓	Nl to ↑	Nl	↑	↑	↑	RBC with Heinz bodies Bite cells Blister cells
Pyruvate kinase deficiency[12]	Mutation in the PKLR and PKM gene Autosomal recessive	Gallstones	Hydrops fetalis Neonatal hyperbilirubinemia Iron overload Perinatal complications	Skin ulcers Splenomegaly	+	Intrinsic	Normochromic	Normocytic	↑	↑	↓	Nl	↑	Nl	Nl	↑	−	Prickle cells Polychromatophilic erythrocytes
Disease	Genetics	History	Symptoms	Signs	Hemolysis	Intrinsic/ Extrinsic	Hb concentration	MCV	RDW	Reticulocytosis	Haptoglobin levels	Hepcidin	Serum iron	Serum Tfr level	IBC	Ferritin	Transferrin saturation	Specific finding on blood smear
Sickle cell anemia[13]	Hbs point mutation causes a single amino acid replacement in β chain	High altitude Low Oxygen Acidosis African-American race Parvovirus B19 infection	Painful crisis Dactylitis Priapism Acute chest syndrome Avascular Necrosis Stroke Autosplenectomy Salmonella osteomyelitis	Dactylitis Priapism	+	Intrinsic	Normochromic	Normocytic	↑	↑	↓	Nl or moderately ↑	Nl	Nl	Nl or moderately ↑	↓	Nl	Increased erythropoiesis Howell-Jolly bodies Anisocytosis
HbC disease[14]	Glutamic acid–to-lysine mutation in β-globin	Gallstone	Joint pains Increased risk of infections	Splenomegaly Cholelithiasis Avascular necrosis of the femoral head	+	Intrinsic	Normochromic	Normocytic	↑	↑	↓	Nl	Nl	Nl	Nl	↓	−	Hemoglobin crystals inside RBCs Target cells
Paroxysmal nocturnal hemoglobinuria[15][16]	PIGA gene mutations Impaired synthesis of GPI anchor for decay-accelerating factor	Associated with aplastic anemia Thrombosis	Fatigue Chest pain Dyspnea on exertion Headache	Chronic hemolysis Hepatomegaly Ascites Papilledema Skin nodules	+	Intrinsic	Normochromic	Normocytic	↑	↑	↓	Nl	↓	Nl	↑	↓	−	NA
Hereditary spherocytosis[17]	Mutations in Ankyrin, Band 3, Protein 4.2, and spectrin	Associated with parvovirus B19 Cholelithiasis Megaloblastic crisis	Aplastic crisis	Splenomegaly	+	Intrinsic	Normochromic	Normocytic	↑	↑	↓	Nl	↓	Nl	↑	Nl	−	Small, round RBCs with less surface area and no central pallor
Disease	Genetics	History	Symptoms	Signs	Hemolysis	Intrinsic/ Extrinsic	Hb concentration	MCV	RDW	Reticulocytosis	Haptoglobin levels	Hepcidin	Serum iron	Serum Tfr level	IBC	Ferritin	Transferrin saturation	Specific finding on blood smear
Microangiopathic hemolytic anemia[18][19]	−	Associated with DIC TTP HUS SLE HELLP syndrome Hypertensive emergency	Purpura Confusion Aphasia Diplopia	Numbness of an arm or hand Jaundice Pale conjunctiva	+	Extrinsic	Normochromic	Normocytic	↑	↑	↓	Nl	↓	Nl	−	↑	−	Helmet cells
Macroangiopathic hemolytic anemia[20]	Autoimmune	Associated with Prosthetic heart valves Aortic stenosis	Pallor Fatigue	Signs of anemia Complications of hemolysis Decreased vascular volume	+	Extrinsic	Normochromic	Normocytic	↑	↑	↓	Nl	↓	Nl	−	−	−	Spherocytes or schistocytes
Autoimmune hemolytic anemia[21]	−	Associated with: SLE CLL Mycoplasma pneumonia	Painful blue fingers and toes on exposure to cold temperature Chest pain Chills Dizziness Tachycardia Headache Fatigue	Painful, blue fingers and toes with cold weather	+	Extrinsic	Normochromic	Normocytic	↑	↑	↓	Nl	↓	Nl	−	−	−	RBC agglutination
Aplastic anemia[22]	Constitutive expression of Tbet Mutations in the perforin gene Mutations in SAP gene	Exposure to Radiation Drugs like Benzene, chloramphenicol, alkylating agents Viral infections like EBV, HIV, Hepatitis Fanconi anemia Idiopathic like Immune mediated, primary stem cell defect	Symptoms based on underlying condition	Short stature Cafe-au-lait spots Thumb defects Radial defects	−	−	Normochromic	Normocytic	↑	↓	Nl	Nl	↓	↓	Nl	↑	↓	Pancytopenia Fatty infiltration
Disease	Genetics	History	Symptoms	Signs	Hemolysis	Intrinsic/ Extrinsic	Hb concentration	MCV	RDW	Reticulocytosis	Haptoglobin levels	Hepcidin	Serum iron	Serum Tfr level	IBC	Ferritin	Transferrin saturation	Specific finding on blood smear
Folate deficiency[23]	Impaired DNA synthesis	Alcohol consumption History of using drugs like methotrexate, trimethoprim, and phenytoin Low socioeconomic groups with poor nutrition Older people Pregnant and lactating women	No neurological symptoms vs B12 deficiency Odynophagia Angular stomatitis	Glossitis Signs of heart failure Anencephaly and spina bifida	−	−	Anisochromic	Macrocytic	↑	↓	Nl	Nl	↑	↑	↓	↑	↑	RBC macrocytosis Hypersegmented neutrophils Pancytopenia in severe cases
Vitamin B12 deficiency[24]	Impaired DNA synthesis	Pernicious anemia Crohn’s disease Gastrectomy Veganism Diphyllobothrium latum infection	Psychosis Insomnia Depression Cognitive slowing Restless leg syndrome	Neurological deficit Myelopathy Memory loss with reduced attention span Nystagmus Positive romberg sign Positive Lhermitte’s sign	−	−	Anisochromic	Macrocytic	↑	↓	Nl	Nl	↑	↑	↓	↑	↑	Senile neutrophil Anisocytosis Ovalocytes
Orotic aciduria[25]	Autosomal recessive Deficiency of enzyme UMPS	Episodic vomiting Rhabdomyolysis	Coma Gastrointestinal manifestation	Neurological manifestation	−	−	Anisochromic	Macrocytic	↑	↓	Nl	Nl	↑	↑	↓	↑	↑	NA
Fanconi anemia[26]	Autosomal recessive X-linked recessive	History of anemia at age 16	Hypopigmentation Cafe-au-lait patches Radial ray anomaly	Significant for bilateral short thumbs	−	−	Anisochromic	Macrocytic	↑	↓	Nl	Nl	↑	↑	↓	↑	↑	Nl appearing WBC, RBC and Platelets But the number is greatly reduced
Disease	Genetics	History	Symptoms	Signs	Hemolysis	Intrinsic/ Extrinsic	Hb concentration	MCV	RDW	Reticulocytosis	Haptoglobin levels	Hepcidin	Serum iron	Serum Tfr level	IBC	Ferritin	Transferrin saturation	Specific finding on blood smear
Diamond-Blackfan anemia[27]	Mutations in: RPL5 RPL11 RPL35A RPS7 RPS10 RPS17 RPS19 RPS24 RPS26	Associated with myelodysplastic syndrome Increased risk of AML	Pale skin Sleepiness Heart murmurs	Triphalangeal thumbs Short stature Microcephaly Hypertelorism Ptosis Micrognathia	−	−	Anisochromic	Macrocytic	Nl	↓	Nl	Nl	↑	↑	↓	↑	↑	NA
Infections[28]	−	Associated with Malaria Babesia	Fever	Fever Signs of shock Headache	+	Extrinsic	Normochromic	Normocytic	↑	↑	↓	Nl	Nl	Nl	−	−	−	Trophozoite Maltese crosses
Chronic kidney disease[29]	−	Pericarditis Encephalopathy Rectal incontinence Decreased libido Restless leg syndrome	Polyuria Hematuria Edema	Hypertension	−	−	Normochromic	Normocytic	↑	Nl/↑	Nl	↑	↓	−	↓	↑	↓	Nl
Liver disease[30]	−	Hepatitis Binge drinking Gall bladder disease	Jaundice Abdominal pain Itchy skin	Ascites Right upper quadrant pain Hepatomegaly Swelling in the legs Ankle swelling	−	−	Anisochromic	Macrocytic	↑	↑	Nl	Nl	↑	↑	↓	↑	↑	Round macrocytes Target macrocytes
Alcoholism[31]	−	History of increased alcohol intake Folic acid deficiency	Memory impairment Nausea Sweating	Truncal obesity Asterixis Encephalopathy Spider angiomas Hematemesis Gynecomastia	−	−	Anisochromic	Macrocytic	↑	↑	Nl	Nl	↑	↑	↓	↑	↑	Oval macrocytes Hypersegmented neutrophils
Disease	Genetics	History	Symptoms	Signs	Hemolysis	Intrinsic/ Extrinsic	Hb concentration	MCV	RDW	Reticulocytosis	Haptoglobin levels	Hepcidin	Serum iron	Serum Tfr level	IBC	Ferritin	Transferrin saturation	Specific finding on blood smear

The 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. The prevalence of DBA is approximately 5000 cases worldwide. 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. There is no racial predilection to DBA. DBA affects men and women equally.

The 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.^[1]

DBA is a rare disease. It is approximately 5000 cases worldwide.

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.

There is no racial predilection to DBA.

DBA affects men and women equally.^[2]

Common risk factors in the development of DBA include positive family history, having a known genetic cause.

• Positive family history of DBA
• Have a known genetic cause, although the cause cannot be detected, in some cases.

DBA typically present with common symptoms of anemia, including pale skin, sleepiness, irritability, tachycardia. Common complications of DBA include physical abnormalities, Cancer predisposition, eye problems such as cataracts, glaucoma, or strabismus, kidney abnormalities, hypospadias, and secondary complications due to standard therapies( Corticosteroids treatment, Red cell transfusion, Bone marrow transplantation). Prognosis is relatively good, overall actuarial survival is 75% at age 40 years

• 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.^[1][2]The severity of Diamond-Blackfan anemia may vary, even within the same family.

• Common complications of Diamond-Blackfan anemia include:
• Physical abnormalities
• higher-than-average chance of developing myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), bone cancer (osteosarcoma), colon cancer^[3]
• Eye problems such as cataracts, glaucoma, or strabismus
• kidney abnormalities
• hypospadias
• Secondary complications due to standard therapies( Corticosteroids treatment, Red cell transfusion, Bone marrow transplantation):
  • Oragans involvement due to 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 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. ^[4]

• Ultimately, 40% of case subjects remain dependent upon corticosteroids which increase the risk of heart disease, osteoporosis, and severe infections. ^[5]
• 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.^[6]