1. Diamond-Blackfan Anemia vs Transient Erythroblastopenia of Childhood
Samin Alavi,
Associate professor,
PCHD-RC, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Neonatal Hematology Congress, Shahrivar 96, Tehran, Iran.

2. Diamond Blackfan Anemia
Recognize the clinical, molecular, and laboratory manifestations of
“Diamond-Blackfan Anemia ”

3. Diamond Blackfan Anemia
DBA is a pure red cell aplasia that is usually recognized in early infancy, associated with a reduction in or an absence of erythroid precursors in bone marrow, variable congenital anomalies, and a predisposition to malignant disease.
Diamond-Blackfan anemia red cells characteristically have increased ADA activity in % of patients.
In more than 90% of patients with DBA, the diagnosis is made before the age of 1 year, but in rare cases severe anemia may develop in utero (nonimmune hydrops fetalis) or later in life.
The median age at diagnosis is 8 weeks of age.
patients present in early childhood with profound macrocytic or normocytic anemia, reticulocytopenia, and a reduction or an absence of erythroid precursors in bone marrow.

4. The lack of red cell precursors can be mild to moderate or severe
The lack of red cell precursors can be mild to moderate or severe. In this severe example, only a single late orthochromatic normoblast is present (arrow). All other cells are either myeloid elements or lymphocytes. It is usually the severe lack of late precursors than very early precursors.

5. 3 diagnostic criteria + 1 major OR 2 minor
Diamond-Blackfan anaemia (DBA) is an inherited disease characterized by pure erythroid aplasia that has been tagged as a “ribosomopathy”
Non classic DBA:
3 diagnostic criteria + 1 major OR 2 minor
2 diagnostic criteria + 2 major OR 3 minor

6. Paucity of erythroid precursors in marrow Major supporting criteria:
Diagnostic Criteria:
Age < 1 yo
Macrocytic anemia
Reticulocytopenia
Paucity of erythroid precursors in marrow
Major supporting criteria:
The presence of a gene mutation associated with DBA
Positive family history
Minor supporting criteria
Elevated eADA activity
Congenital anomalies
Elevated Hemoglobin F
No evidence of other inherited bone marrow failure syndrome
probable diagnosis of Diamond-Blackfan anemia :
Three diagnostic criteria and a positive family history
Two diagnostic criteria and three minor criteria
A positive family history and three minor criteria
Non classical DBA is diagnosed when there is a DBA associated gene mutation but insufficient diagnostic criteria

7. DBA: Congenital Anomalies
Are seen in at least 47% of all patients
- 50% cranioorofacial (tow colored hair, blue sclerae, glaucoma, cleft palate)
- 38% upper extremity (thumbs, may be subtle)
39% genitourinary
30% cardiac
Over 20% with more than one anomaly
Short stature and bony abnormalities common, and often overlooked!

9. e ADA activity
ADA activity in patients with DBA was greater than that seen in:
Cord blood
Hemolytic anemia
Acquired aplastic anemia
Fanconi anemia,
Acquired pure red-cell aplasia,
Transient erythroblastopenia of childhood.
Adenosine deaminase activity may be a unique marker for identifying DBA
e ADA has a sensitivity of 84% and specificity 95%,
16% of patients with classical clinical DBA had a normal eADA
Br J Haematol Feb;160(4):  

10. DBA: Genetics Autosomal dominant, Autosomal recessive
May be sporadic (2/3) or familial (1/3)
Mutations/deletions in ribosomal proteins genes are observed in 70% of patients.
RP S19 (DBA 1) in 25% of patients
- RP L5, RP S10, RPL 11, RP L35a, RP S26, RP S24, RP S 17, RP S7, RP L19, RP L 26
25-40% of patients have unknown mutations
Mutations in RP S19 is associated with a decrease in proliferation of progenitor cells but normal terminal erythroid differentiation,
Mutations in RP L11 is associated with a decrease in progenitor cell proliferation and delayed erythroid differentiation with a marked increase in apoptosis.

11. Gene
% of DBA Attributed to  Pathogenic Variants in This Gene
RPL5
~6.6%
RPL11
~4.8%
RPL35A
~3%
RPS10
~2.6%
RPS17
~1%
RPS19
~25%
RPS24
~2%
RPS26
~6.4%

12. In some individuals with DBA , the anemia is transient; however, the macrocytosis and elevated ADA levels often persist.
Spontaneous remission of anemia in DBA patients has been reported in 20-30% , even after years of steroid or transfusion dependence
Thrombocytosis (platelet counts > 1 ,000,000 rarely) and decreased platelet counts have also been reported.
WBCs are generally normal but in some cases leukopenia is present.
In rare cases DBA progresses to the full clinical picture of severe aplastic anemia.
Dyserythropoietic morphology, including ringed sideroblasts, have rarely been reported.

13. DBA: Treatment of anemia
Prednisone:
2 mg/kg for up to 8-12 weeks before diagnosis of failure ,Taper to minimum dose to maintain Hgb > 9 g/dl
60-70 % steroid responsive
Glucocorticoid treatment increases the erythropoietin sensitivity of both normal and DBA erythroid progenitors, but DBA erythropoietic differentiation and maturation remains suboptimal
For steroid-refractory patients or those requiring high doses of steroids, consider chronic red cell transfusions
Metoclopramide, CSA, IL-3 , Androgens, Valproic acid
Leucine ( mTor activator , induces protein metabolism and synthesis) ….

14. Pure red cell aplasia is morphologically characterized by severe lack of erythroid precursors , whereas myeloid precursors and megakaryocytic elements are unaffected and are present in normal numbers.

15. DBA Outcomes Remission of anemia : 20% by age 25
No genetic or clinical feature predicts of remission.
HSCT for transfusion-dependent patients, particularly those who are
alloimmunized or have OTHER cytopenias (neutropenia) is recommended.
HSCT Does not cure solid tumor risk
The sibling donor needs careful evaluation for DBA

16. Diamond Blackfan Anemia…. Malignancy
30 Cases* Reported in the Literature
AML/MDS 15
ALL 1
Osteosarcoma 6
Hodgkin disease/NHL 3
Breast carcinoma 2
Hepatocellular carcinoma 2
GI carcinoma 2
Melanoma 1
Malignant fibrous histiocytoma 1
Soft tissue sarcoma 1
Non-Hodgkin Lymphoma 1
From Alter, BP. In Shimamura and Alter, Blood Reviews, 2010

17. Differential Diagnosis of Childhood Pure Red Cell Aplasia
Congenital: Pearson syndrome, SDS, FA, DC, CHH
Acquired:
Immune pure red cell aplasia
Transient erythroblastopenia of childhood (TEC)
Infection associated – parvovirus
Collagen vascular disease/autoimmune associated
Thymoma
Pregnancy
Severe renal failure, nutritional
Drugs or Toxins

18. Transient Erythroblastopenia of Childhood (TEC)
Although it has been diagnosed in children as young as 1 month old, it usually presents in children 6 months – 6 years old, particularly between the ages of 1 and 4 years.
It is more common in males than in females.
The incidence of TEC is difficult to estimate since it is likely that most cases are subclinical,

19. Transient Erythroblastopenia of Childhood (TEC)
The etiology for suppression of erythropoesis in TEC remains unknown, environmental exposures, viral illness, and genetic predisposition have been proposed.
While parvovirus B19 is known to cause red cell aplasia in children with hemolytic anemia, no association has been found with TEC in multiple studies.
Multiple case series have suggested that there is an association with an antecedent viral URI or gastroenteritis 2-3 months prior to symptom onset, although there is no seasonal clustering.
No specific mutation or affected gene was identified in TEC.

20. Transient Erythroblastopenia of Childhood (TEC)
Typically self limited – close supportive care
Transfusion if necessary in Hgb < 5 with reticulocytopenia
Follow-up to resolution
Findings on CBC:​
Normochromic/ Normocytic anemia (Absence of macrocytosis)
During the recovery phase, RBCs become transiently macrocytic
​Reticulocytopenia (<3%) and then reticulocytosis in recovery
Normal WBC
Mild neutropenia in 20-50%
​Normal platelets or thrombocytopenia

21. Diamond Blackfan Anemia vs Transient Erythroblastopenia of Childhood
DBA TEC
History: Inherited Acquired
Physical Anomalies: % none
Laboratory:
Hb : gr gr
ANC < 1000/µl % %
Plts > 400,000 /µl % %
plts < 100,000 /µl % %

22. DBA vs TEC E ADA increased: 85- 90% 0% MCV increased:
DBA TEC
E ADA increased: % %
MCV increased:
At diagnosis 80% 20%
During recovery 100% 90%
In remission % 0%
Hb F increased
At diagnosis 100% 25%
During recovery % 100%
In remission % 0%

23. Aplastic Crisis in Hemolytic Anemia
May resemble TEC or DBA, if no prior diagnosis of a hemolytic anemia
Acquired pure red cell aplasia:​
TEC
Infectious (parvovirus, hepatitides, EBV, HIV, HHV6, echovirus)
​Drug associated (AEDs, sulfonamides, isoniazid, azathioprine, procainamide)
Rheumatologic (SLE, JIA)
Autoimmune
Thymoma, lymphoid malignancies