Diamond-Blackfan anemia overview
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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
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.
Historical Prespective
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.
Pathophysiology
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.
Causes
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.
Differentiating Diamond-Blackfan Anemia from Other Diseases
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).
Epidemiology and Demographics
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.
Risk Factors
Common risk factors in the development of DBA include positive family history, having a known genetic cause.
Screening
There is no routine screening.
Natural History, Complications, and Prognosis
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
Diagnosis
Study of Choice
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.
History and Symptoms
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.
Physical Examination
Common physical examination findings of DBA include signs of anemia such as pallor, tachycardia, and congenital abnormalities.
Laboratory Findings
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.
Electrocardiogram
There are no ECG findings associated with DBA. However, an ECG may be helpful in the diagnosis of related-therapies complications of DBA.
X-ray
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.
Echocardiography and Ultrasound
Renal ultrasound and echocardiography should be done to diagnosis any renal or cardiac abnormalities.
CT scan
There are no CT scan findings associated with DBA. It can use for the diagnosis of congenital physical abnormalities.
MRI
There are no MRI findings associated with DBA. It can use for the diagnosis of congenital physical abnormalities.
Other Imaging Findings
There are no other imaging findings associated with DBA.
Other Diagnostic Studies
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.
Treatment
Medical Therapy
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.
Surgery
Corrective surgery can be performed for the correction of congenital abnormalities.
Future or investigational therapies
Researchers still want to know why steroids often work in DBA, find more mutations, and address some questions about Diamond-Blackfan anemia.
References