Diamond- Blackfan Anemia - PowerPoint Presentation

Slide1

Diamond-Blackfan AnemiavsTransient Erythroblastopenia of Childhood

Samin

Alavi

,

Associate professor,

PCHD-RC,

Shahid

Beheshti

University of Medical Sciences, Tehran, Iran.

Neonatal Hematology Congress, 22-24

Shahrivar

96, Tehran, Iran.

Slide2

Diamond Blackfan Anemia

Recognize the clinical, molecular, and laboratory manifestations of

“Diamond-

Blackfan

Anemia

”

Slide3

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 80-90 % 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.

Diamond

Blackfan

Anemia

Slide4

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.

Slide5

Non classic DBA: 3 diagnostic criteria + 1 major OR 2 minor2 diagnostic criteria + 2 major OR 3 minorDiamond-

Blackfan

anaemia

(DBA) is an inherited disease characterized by pure erythroid aplasia that has been tagged as a “ribosomopathy”

Slide6

Diagnostic Criteria: Age < 1 yo Macrocytic anemia

Reticulocytopenia

Paucity

of

erythroid precursors in marrowMajor supporting criteria: The presence of a gene mutation associated with DBA Positive family historyMinor supporting criteriaElevated eADA activityCongenital anomalies Elevated Hemoglobin FNo 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

Slide7

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% genitourinary30% cardiacOver 20% with more than one anomalyShort stature and bony abnormalities common, and often overlooked

!

Slide8

Slide9

e ADA activity

ADA

activity in

patients with DBA was

greater than that seen in: Cord blood Hemolytic anemiaAcquired aplastic anemiaFanconi 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

B

r

J Haematol. 2013 Feb;160(4):547-54. 

Slide10

DBA: GeneticsAutosomal dominant, Autosomal recessiveMay 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.

Slide11

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%

Slide12

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

.

Slide13

DBA: Treatment of anemiaPrednisone: 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 suboptimalFor steroid-refractory patients or those requiring high doses of steroids, consider chronic red cell transfusionsMetoclopramide

, CSA, IL-3 , Androgens,

Valproic

acid

Leucine

(

mTor

activator , induces protein metabolism and synthesis)

….

Slide14

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.

Slide15

DBA OutcomesRemission of anemia : 20% by age 25No 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 riskThe sibling donor needs careful evaluation for DBA

Slide16

Diamond Blackfan Anemia…. Malignancy30 Cases* Reported in the Literature AML/MDS 15

ALL 1

Osteosarcoma 6

Hodgkin disease/NHL 3

Breast carcinoma 2Hepatocellular carcinoma 2GI carcinoma 2Melanoma 1Malignant fibrous histiocytoma 1Soft tissue sarcoma 1Non-Hodgkin Lymphoma 1

From Alter, BP. In Shimamura and Alter, Blood Reviews, 2010

Slide17

Differential Diagnosis of Childhood Pure Red Cell AplasiaCongenital: Pearson syndrome, SDS, FA, DC, CHHAcquired

:

Immune pure red cell aplasia

Transient

erythroblastopenia of childhood (TEC)Infection associated – parvovirusCollagen vascular disease/autoimmune associatedThymomaPregnancy Severe renal failure, nutritional

Drugs or Toxins

Slide18

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,

Slide19

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.

Slide20

Transient Erythroblastopenia of Childhood (TEC)Typically self limited – close supportive careTransfusion 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 recoveryNormal WBCMild neutropenia in 20-50%​Normal platelets or thrombocytopenia

Slide21

Diamond Blackfan Anemia vs Transient Erythroblastopenia of Childhood

DBA

TECHistory: Inherited AcquiredPhysical Anomalies: 50% noneLaboratory: Hb : 1.2-10.0 gr 2.4-10.6 gr ANC < 1000/µl 20%

10

%

Plts

>

400,000

/

µl

20% 50%

plts

<

100,000

/

µl

10%

5

%

Slide22

DBA vs TEC DBA TECE ADA increased: 85- 90% 0

%

MCV

increased:

At diagnosis 80% 20% During recovery 100% 90% In remission 100% 0%

Hb

F

increased

At

diagnosis 100% 25%

During

recovery

100

%

100%

In

remission

85

%

0

%

Slide23

Aplastic Crisis in Hemolytic AnemiaMay 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)AutoimmuneThymoma, lymphoid malignancies