Bone marrow nonneoplastic
Alterations in cellularity
Diamond-Blackfan anemia
Author: Guang "Geoff" Yang, M.D., Ph.D.
Last author update: 1 March 2017
Last staff update: 12 July 2019
Copyright: 2003-2019, PathologyOutlines.com, Inc.
PubMed Search: Bone marrow Diamond-Blackfan anemia [title]
Table of Contents
Definition / general | Terminology | Essential features | Epidemiology | Pathophysiology | Diagrams / tables | Clinical features | Diagnosis | Laboratory | Prognostic factors | Case reports | Treatment | Microscopic (histologic) description | Peripheral smear description | Molecular / cytogenetics description | Differential diagnosisCite this page: Yang G. Diamond-Blackfan anemia. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/bonemarrowdiamondblackfan.html. Accessed January 10th, 2025.
Definition / general
- A member of the inherited bone marrow failure syndromes (BMFS); typically shows an onset in the first year of life (Br J Haematol 2016;172:782)
- Main features include normochromic macrocytic anemia, reticulocytopenia and nearly absent erythroid progenitors in the bone marrow (OMIM: Diamond-Blackfan Anemia 1)
- Predisposition to acute myelogenous leukemia, myelodysplastic syndrome and solid tumors
Terminology
- Also known as Blackfan-Diamond anemia, congenital hypoplastic anemia and inherited erythroblastopenia (Eur J Hum Genet 2013 Oct;21(10))
Essential features
- Also known as Blackfan-Diamond anemia, congenital hypoplastic anemia and inherited erythroblastopenia
- A member of the inherited bone marrow failure syndromes (BMFS); typically shows an onset in the first year of life (Br J Haematol 2016;172:782)
- Underlying defect hypothesized to be faulty ribosome biogenesis, resulting in proapoptotic erythropoiesis and erythroid failure (Hematol Oncol Clin North Am 2009;23:261)
- Growth retardation and various congenital abnormalities commonly seen
- Normochromic macrocytic anemia, reticulocytopenia, normocellular for age marrow and nearly absent erythroid progenitors in the bone marrow (OMIM: Diamond-Blackfan Anemia 1)
- Predisposition to acute myelogenous leukemia, myelodysplastic syndrome and solid tumors
Epidemiology
- Incidence 1:100,000 ~ 1:200,000 live births and remains consistent across ethnicities (GeneReviews: Diamond-Blackfan Anemia)
- Males and females equally affected
- ~90% diagnosed within first year of life and 35% diagnosed within first month
Pathophysiology
- ~55% are sporadic cases; ~45% familial with disease inherited mostly in an autosomal dominant pattern
- Incomplete penetrance (GeneReviews: Diamond-Blackfan Anemia)
- Underlying defect hypothesized to be faulty ribosome biogenesis, resulting in proapoptotic erythropoiesis and erythroid failure (Hematol Oncol Clin North Am 2009;23:261)
- Heterozygous mutations in ribosomal proteins (RPs) encoding genes, both small and large ribosomal subunit, have been identified in 60% (Br J Haematol 2016;172:782)
- Mutations identified in 15 RP genes: RPS7, RPS10, RPS17, RPS19, RPS24, RPS26, RPS27, RPS29, RPL5, RPL11, RPL15, RPL26, RPL27, RPL31, RPL35A (Br J Haematol 2016;172:782)
Diagrams / tables
Images hosted on other servers:
Hypothetic model for abortive
ribosome assembly and p53
activation relevant to DBA
Clinical features
- Pallor, weakness, failure to thrive (GeneReviews: Diamond-Blackfan Anemia)
- Growth retardation and various congenital abnormalities seen in 30% - 50%, in particular craniofacial, upper limb, heart and genitourinary malformations
- Higher risk for developing certain malignancies including acute myelogenous leukemia, myelodysplastic syndrome and solid tumors
Diagnosis
-
According to 6th Annual Diamond-Blackfan anemia (DBA) International Consensus Conference (Br J Haematol 2008;142:859)
- Classic Diamond-Blackfan anemia is diagnosed if all of the following diagnostic criteria are met:
- Age < 1 year
- Macrocytic anemia with no other significant cytopenias
- Reticulocytopenia
- Normal marrow cellularity with a paucity of erythroid precursors
- A probable diagnosis is made based on the following major and minor supporting criteria, if all of the above diagnostic criteria cannot be met :
- Major supporting criteria:
- The presence of a gene mutation associated with DBA
- Positive family history
- Minor supporting criteria
- Elevated eADA activity
- Congenital anomalies associated with DBA
- Elevated Hemoglobin F
- No evidence of another inherited bone marrow failure syndrome
- A probable diagnosis of Diamond-Blackfan anemia can be made in the following settings:
- Three diagnostic criteria and a positive family history
- Two diagnostic criteria and three minor criteria
- A positive family history and three minor criteria
- Major supporting criteria:
- Nonclassical DBA is diagnosed when there is a DBA associated gene mutation but insufficient diagnostic criteria
Laboratory
- Macrocytic anemia with no other significant cytopenias (GeneReviews: Diamond-Blackfan Anemia)
- Increased red cell mean corpuscular volume (MCV)
- Reticulocytopenia
- Elevated erythrocyte adenosine deaminase activity (eADA) (observed in 80% - 85%)
- Elevated hemoglobin F (HbF) concentration
Prognostic factors
-
Associated with unfavorable prognosis (Pediatr Res 1999;46:553)
- Young age at presentation
- No family history
- Premature birth
Case reports
- Hydrops fetalis with de novo mutation in RPS19 gene (Am J Hematol 2013;88:160)
- Infant female with multiple congenital midline defects (J Pediatr Hematol Oncol 2007;29:338)
- 3 month old boy with coexisting Johanson-Blizzard syndrome (J Coll Physicians Surg Pak 2010;20:627)
- 7 year old boy with subsequent Hodgkin lymphoma (J Pediatr Hematol Oncol 2006;28:234)
- 10 year old girl with fatal agranulocytosis after deferiprone therapy (Blood 2007;109:5157)
- 16 year old Japanese boy with colon tumors after hematopoietic stem cell transplantation (Int J Clin Exp Pathol 2015;8:5938)
- 17 year old girl with multihormonal hypopituitarism, hypothyroidism and hypoparathyroidism (Pediatr Endocrinol Diabetes Metab 2013;19:111)
- Child with isolated cleft palate (Cleft Palate Craniofac J 2010 Nov 19 [Epub ahead of print])
- Japanese patient with a novel mutation of ribosomal protein S10 gene (J Pediatr Hematol Oncol 2012;34:293)
Treatment
- Corticosteroids and red cell transfusions: mainstays of therapy
- Hematopoietic cell transplantation: for steroid refractory patients (Hematol Oncol Clin North Am 2009;23:261)
- Other therapies: androgens, IL3, metoclopramide and immunosuppressive agents (Blood 2007;109:2266)
Microscopic (histologic) description
- Bone marrow examination usually shows normocellular for age, complete loss of erythroid elements or only scattered isolated erythroblasts
- Increased hematogones, especially in infants and young children
- Granulocytic and megakaryocytic lineages are preserved; mild eosinophilia is often present
Peripheral smear description
- Peripheral blood examination usually shows normochromic, macrocytic red blood cells, mild anisopoikilocytosis and the absence of polychromasia (Proytcheva: Diagnostic Pediatric Hematopathology, 1st Edition, 2011)
Molecular / cytogenetics description
- Most common genetic causes of Diamond-Blackfan anemia (GeneReviews: Diamond-Blackfan Anemia)
Gene % of DBA Attributed to
Pathogenic Variants in This GeneRPL5 ~6.6% RPL11 ~4.8% RPL35A ~3% RPS10 ~2.6% RPS17 ~1% RPS19 ~25% RPS24 ~2% RPS26 ~6.4%
Differential diagnosis
- Acquired conditions with bone marrow failure: infections (Parvovirus B19 infection, HIV, viral hepatitis, mononucleosis and HTLV1), drugs and toxins, immune mediated diseases (thymoma, myasthenia gravis, systemic lupus erythematosus and multiple endocrinopathies)
- Other genetic conditions with bone marrow failure: Fanconi anemia, Shwachman-Diamond syndrome, Pearson syndrome, dyskeratosis congenita, cartilage hair hypoplasia
- Transient erythroblastopenia of childhood (TEC): acquired anemia caused by decreased production of red blood cell precursors in a previously healthy child; self resolving; 80% of children are age one year or older at diagnosis; normocytic anemia
