APLASTIC ANEMIA

AND
PURE RED CELL
APLASIA
SAUMYA GUPTA
DR. MANUPDESH SACHDEVA
 HISTORICAL BACKGROUND
 The disease was first described by Dr. Paul Ehrlich in 1888 in a
young pregnant lady who died of severe anaemia and neutropenia.
On autopsy, the marrow was fatty with no haematopoiesis.

 Chauffard, in 1904, named the disease ‘aplastic anemia’.

 In 1972, first successful allogeneic bone marrow transplantation

was done.
Aplastic anaemia is defined by-

 Pancytopenia.

 Hypocellular bone marrow where normal haemopoietic cells are

replaced by fat.

 In the absence of abnormal or malignant cells or fibrosis.

EPIDEMIOLOGY
 Overall incidence of AA is 2 cases per 1 million people.

 2-3 fold higher in Southeast Asia.

 Acquired AA-15-25 years(maximum incidence).

 After 60 years- second peak.

 M=F

 Inherited AA- first decade of life, associated with physical

anomalies.
 CLASSIFICATION OF AA BASED
ON SEVERITY.
Peripheral blood Bone
counts marrow

cellularity
Severe AA •ANC- <500/mm3 <25%
• Platelets<20,000/mm3
• Reticulocytes
<60,000/mm3 , or

• Corrected retic- <1%

(At least two)

Very severe AA Same as severe AA with <25%

ANC<200/mm3

Non severe AA Do not fulfil criteria for <25%

severe AA
CATEGORIES
 Acquired aplastic anaemia- 80%.

 Inherited aplastic anaemia- 20%.

 ACQUIRED AA- ETIOLOGY
 Idiopathic- Idiosyncratic immune response against haematopoietic stem
cells- in most of the cases.
 Drugs
 Viruses- EBV, seronegative hepatitis (Non-A to Non-G ), HIV,
parvovirus B19.
 Mycobacterial infections.
 Autoimmune/ Connective tissue disorders- RA, eosinophilic
fasciitis, immune thyroid diseases, SLE.
 Thymoma.
 Pregnancy-Relapse in women, treated with immunosuppressives
for AA.

 Iatrogenic- Ionising radiation, cytotoxic therapy.

 Benzene
PATHOGENESIS
 The final common pathway is a decrease in blood cell formation
in the marrow.

 Marked reduction in
1. CD34+ multipotential hemopoietic progenitor cells.
2. Their derivatives- CFU-GM and BFU-E.
(However, some healthy stem cells still persist and there can be a
complete recovery of haematopoiesis, after immunosuppressive
therapy. )
Mechanisms responsible-
 Cell- mediated or humoral immune suppression.
 Direct toxic effects on hemopoietic progenitor cells.
 Defect in stromal microenvironment of the marrow-important
for cell development.
 Impaired production of essential multi-lineage growth factors.
ROLE OF AUTOREACTIVE
CYTOTOXIC T-CELLS
 Constitutive activation of T-bet and low SAP levels in the T-cells
in AA.

 T-bet- a transcription factor, binds to IFN-gamma promoter region

and induces gene expression.

 SAP, a SLAM-associated protein, modulates SLAM activity on

IFN-gamma expression, diminishing the gene transcription.

 There is overproduction of IFN-gamma and TNF-alpha, which

directly inhibit hematopoiesis and upregulate Fas on CD34+
cells.
 A decrease in the T- regulatory cells- expansion of autoreactive
CD8+,CD28-Tcell population- apoptosis of autologous
hemopoietic multipotential progenitor cells.

 Humoral immune response in AA- In 40% patients,

autoantibodies against kinectin expressed on haemopoietic cells.
 ROLE OF VIRUSES
 Direct cytotoxic effect on hemopoietic progenitor cells.
 Immune response through activation of cytotoxic T-cells or cell
surface expression of viral proteins or epitope sharing leading to
autoimmunity.
 Infection of stromal cells, which compromises the bone marrow
microenvironment, diminishing the hematopoiesis.
 Responds to immunosuppressive therapy.
AUTOIMMUNE DISEASES
 Through antibody or suppressor cells.
 Drugs used to treat RA like gold, D- penicillamine, NSAIDs.
 MICROENVIRONMENT
 Inability of the bone marrow stroma to support hematopoiesis has
been proposed as a potential mechanism underlying aplastic
anemia.
 Most patients transplanted for aplastic anemia are cured with
allogeneic donor stem cells and autologous stroma, which very
well supports the donor stem cells.
 Circulating levels of erythropoietin, G-CSF and GM-CSF,
thrombopoietin, and flt-3 ligand are elevated in patients with
aplastic anemia.
CLINICAL FEATURES.
 Gradual onset
 Pallor, weakness, fatigue, dyspnea
 Dependent petechiae, bruising, epistaxis, vaginal bleeding,
unexpected bleeding at other sites.
 Fever, chills, pharyngitis.
 Lymphadenopathy and splenomegaly are not seen.
DIAGNOSTIC APPROACH
 Full blood count -Diagnosis and severity criteria.
 Reticulocyte count (automated or microscopic counting) -
Diagnosis and severity criteria
 Peripheral blood film examination- Differential diagnosis.
 Morphology- Abnormal cells/blasts
 BM aspirate –Diagnosis, differential diagnosis and prognosis
1. Morphology- malignant disease, storage disease,
haemophagocytosis.
2. Cytogenetics with optional FISH-analysis(search for 7; þ8,
5q-, and so on for MDS)
3. Immunophenotyping- Monoclonal B/T cells, blasts, dysplastic
cells.
4. Culture.
5. DNA/antigen-based viral tests
Trephine biopsy
 Assess cellularity
 Infiltrative or malignant disease
 Storage disease
 Fibrosis or granuloma.
 CD34 and CD117 immunostaining- blast detection.
 PNH work up- flow-cytometry.
 PCR for Hepatitis viruses and Parvovirus B19.
 Liver function tests.
 Auto-antibody screen.
 Vitamin B12, folic acid assay –Megaloblastic anaemia.
 Iron status, fibrinogen- Hemophagocytosis syndrome.
 Serum bilirubin and LDH.
OTHER TESTS
 Chest X-ray- Infection.
 USG abdomen- Splenomegaly, lymphadenopathy.
 Vertebral MRI- Uniformly fatty in AA , mixture of hypo- and
hyperdense cellular marrow in MDS.
 HLA-typing – HSCT.
PANCYTOPENIA WITH
HYPOCELLULAR MARROW
 Acquired aplastic anaemia
 Inherited aplastic anaemia
 Hypoplastic MDS
 Large granular lymphocytic leukemia
 Hypoplastic PNH
APLASTIC ANEMIA V/S HYPOPLASTIC
MDS
Features AA Hypoplastic MDS
 Cytopenia Present Present
 BM cellularity Aplastic or hypocellular Hypocellular

 BM hematopoiesis
 Erythropoiesis Present in nest, ‘hot spots’ Present
 Myelopoiesis Typically decreased Present
 Megakaryopoiesis Decreased or absent Present

 Dysplasia
 Erythropoiesis Possible Possible
 Myelopoiesis Normal morphology Possible
 Megakaryopoiesis Normal morphology Possible

 Blasts Absent Variable

 CD34 or CD117 cells Nearly absent Normal or increased
 Marrow fibrosis Absent Possible
 Karyotype Clonal abnormality (about 12%) - 7/del(7q),-5/del(5q)
 PNH clone Frequent Unusual
 Splenomegaly at diagnosis Absent Possible
(Rovo et al, Bone Marrow Transplantation, 2013)
AA AND MDS
 As many as 15 to 20 percent of patients with aplastic anemia have
a 5-year probability of developing myelodysplasia.
(Socie et al, Semin hematol, 2000).
 Telomere shortening may play a pathogenetic role in the evolution
of aplastic anemia into myelodysplasia.
 The frequency of a clonal disorder was nearly 15 times greater in
patients of AA treated with immunosuppression as compared to
those treated with marrow transplantation after 39 months of follow-
up. (Socie et al, N Engl J Med,1993)

 The development of monosomy 7 (most common) or trisomy 8

portends the evolution of a myelodysplastic syndrome or acute
leukemia.

 Disappearance of monosomy 7- hematologic improvement.

(Socie, Semin Hematol, 2000)
 Persistence of Monosomy 7 carries a poor prognosis than Trisomy
8. (Maciejewski et al, Blood, 2002)
Aplastic
anemia-
hypocellular
marrow, with
few erythroid
precursors

MDS-
Hypocellular
marrow, with
blasts
AA AND PNH
 More than 50 percent of patients with aplastic anemia may have a
PNH cell population as detected by immunophenotyping.
(Shrezenmeier H et al, Exp Hematol1995)
 The PIG-A mutation may confer either a proliferative or survival
advantage to PNH cells.
(Nakakuma et al, Int J Hematol, 2003)
 Pediatric AA patients: Data from PGI
 Nine (12.9%) out of 70 patients had PNH clones comprising >1%
of the target cell population, including five patients (7.14%) with
PNH clone size >10%.
 A lower frequency but moderate/large-sized PNH clones were
seen in our pediatric AA population.
 Sreejesh Sreedharanunni et al. Pediatric Blood & Cancer, 2016
TREATMENT OF AA
Supportive- Discontinue any potential offending drug and use an
alternative class of agents if essential.
 Anemia: transfusion of leukocyte-depleted, irradiated red cells as
required for very severe anemia.
 Very severe thrombocytopenia or thrombocytopenic bleeding:
consider -aminocaproic acid; transfusion of platelets as required.
 Severe neutropenia; use infection precautions.
 Fever (suspected infection): microbial cultures; broad-spectrum
antibiotics and G-CSF.

 Immediate assessment for allogeneic stem cell transplantation:

Histocompatibility testing of patient, parents, and siblings.
BONE MARROW
TRANSPLANTATION
 BMT from an HLA identical sibling is indicated as first-line
therapy -
 If the patient has severe or very severe disease and
 Younger than 40 years of age.
 An immunosuppressive, non-myeloablative preparative regime-
prevents graft rejection (cyclophosphamide 200 mg/kg with
antithymocyte globulin (ATG)).
 Cyclosporin and methotrexate are used to prevent graft versus
host disease.
 Success rate is good- 70–90% chance of long-term cure for
patients younger than 40 years of age.
 Combination of ATG and cyclosporin is indicated for-
 All patients over 40 years old.
 All those with non-severe disease.
 Younger patients with severe or very severe disease who lack
an HLA compatible sibling donor.
 Although 60–80% will respond and achieve normal or near-
normal blood counts, recovery is unstable.
 Relapse may occur in 10–30%, necessitating further
immunosuppression, approximately 10% later develop PNH, and
a further 10% MDS or acute myeloid leukaemia.
Survival of 2479 patients with acquired severe aplastic anemia according to whether their
first-line treatment was BMT or immunosuppression: the 10-year survival is 73% in BMT
recipients and 68% in those treated with immunosuppression (p=0.002). Anna Locasciulli et al.
Outcome Of Patients With Acquired Aplastic Anemia Haematologica, 2007
 RESPONSE CRITERIA OF
AA
 A complete response (CR)- Normalization of the blood values-
1. Neutrophil count >1.5X109/L.
2. Platelet count > 150X109/L.
3. Hb >120 g/L.
 A partial response (PR) - Transfusion independency in patients
who needed transfusions before treatment, with either
improvement of the severity degree of the AA, or
1. Neutrophil counts > 0.5X109/L.
2. Platelet count >20X109/L, (in case the values were lower before
treatment).
 Non- response- Transfusion dependency or of values lower than
those mentioned above.
( Rovo et al, Bone Marrow Transplantation 2013)
 PROGNOSIS
 At diagnosis, the prognosis is largely related to the absolute
neutrophil and platelet count.
 The absolute neutrophil count is the most important prognostic
feature.
 Combination immunosuppressive therapy with ATG and
cyclosporine leads to a marked improvement in approximately 70
percent of the patients.
 Marrow transplantation is curative for approximately
 80 to 90% of patients younger than 20 years of age,
 70% if between the ages of 20 and 40 years,
 50% if older than age 40 years.
 INHERITED APLASTIC
ANAEMIA
1. Fanconi anaemia

2. Dyskeratosis Congenita

3. Shwachman-Diamond syndrome

4. Congenital Amegakaryocytic Thrombocytopenia

FANCONI ANAEMIA
 Fanconi anemia is the most common form of constitutional
aplastic anemia.
 Initially described in three brothers by Fanconi in 1927.
 Autosomal recessive.

 FA defect was observed in 24.07% patients with bone marrow

failure syndrome (PGIMER)
Varma N, Varma S, Marwaha RK, Malhotra P, Bansal D, Malik K, Kaur S, Garewal G.
(Indian J Med Res. 2006)
PATHOGENESIS
 Thirteen complementation groups, are associated with the
development of Fanconi anemia.
 A complementation group is a genetic subgroup.
 Identifying a complementation group requires adding a gene to
the genome of a cell to correct (complement) the genetic defect.
 The complementation groups have been designated FANC A, B,
C, D1, D2, E, F, G, I, J, L, M, and N.

 Majority - Mutations of FANCA, FANCC, or FANCG.

 Cells from FA patients usually show an abnormally high

frequency of spontaneous chromosomal breakage and
hypersensitivity to the effects of DNA cross-linking agents such
as diepoxybutane (DEB) and mitomycin-C (MMC).
 FA complementation
groups
Frequency
Subtype Gene Inheritance Chromosomal
(%)

A FANCA 60 AR 16q24.3
B FANCB Rare X-R Xp22.31
C FANCC 15 AR 9q22.3
D1 BRCA2 5 AR 13q12.3
D2 FANCD2 5 AR 3p25.3
E FANCE Rare AR 6p21.3
F FANCF Rare AR 11p15
G FANCG 10 AR 9p13
I Unknown Rare AR Unknown
J BRIP1 Rare AR 17q23.2
L FANCL Rare AR 2p16

M FANCM Rare AR 14q21.2

N FANCN Rare AR 16p12.1
Schematic diagram of the Fanconi anemia (FA) pathway. FA proteins (A, B,
C, D1, D2, E, F, G, I, J, L, M, N) are depicted with shaded circles. Additional DNA repair proteins interacting with
the FA pathway are denoted in non-shaded circles. Following activation of the FA core complex by DNA damage or
the cell cycle, the D2 and I proteins are monoubiquitinated.Monoubiquitinated D2/I are translocated to chromatin
where they colocalize with additional DNA repair proteins to participate in interstrand DNA crosslink repair
Additionally associated with
 Solid tumors- squamous cell carcinoma of head and neck, skin,
GIT and genital tract.
 Liver tumors- Androgen treatment.
 MDS and AML(10% by 24 years).
(Rosenberg PS, Blood, 2003)
 Onset of marrow failure is gradual, evident during the last half of
the first decade of life.
LAB DIAGNOSIS
 Random chromatid breaks are present in myeloid cells,
lymphocytes, and chorionic villus biopsy samples.

 This chromosome damage is intensified after exposure to DNA

cross-linking agents such as mitomycin C or diepoxybutane.

 The hypersensitivity of the chromosomes of marrow cells or

lymphocytes to the latter agent is used as a diagnostic test for this
condition.
Chromosomal breakage
test.- At least 50
metaphases are
analysed- Reported as
number of cells with
breaks and radial forms.
THERAPY AND PROGNOSIS
 Androgen preparations and cytokines.
 Allogeneic hematopoietic stem cell transplantation is the current
treatment of choice for the marrow manifestations of Fanconi
anemia.
 The cumulative median survival is about 20 years.
DYSKERATOSIS CONGENITA
 Cutaneous and mucous membrane abnormalities.
 Progressive marrow insufficiency.
 Predisposition to malignant transformation.
 M>F.
 Inheritance- X- linked recessive, AD or AR.
PATHOGENESIS
 Telomere complex dysfunction.

 Defective telomerase activity resulting from mutations in the

telomerase-related genes.
 Telomerase complex maintains the length of telomeres, which are
nucleotide tandem repeat structures residing at the termini of
eukaryotic chromosomes (e.g., 5'-TTAGGG-3').

 Telomerase restores the G-rich telomere repeats that are lost as a

result of end-processing during normal cell division.

 Maintains chromosome integrity by preventing end-to-end

chromosome fusion, preventing chromosome degradation,
prevent chromosome instability.
 In DK, the telomeres are markedly shortened resulting in genomic
instability and cell (including marrow cell) apoptosis.

 Rapidly proliferating cells are at highest risk for dysfunction.

 Inheritance pattern Gene
 X- linked DKC-1
 Autosomal dominant TERC,TERT,TINF2
 Autosomal recessive NOP10,NHP2
CLINICAL FINDINGS
 Skin- Reticulated, tan to gray, hyperpigmented and
hypopigmented cutaneous macules; alopecia of scalp, eyelashes,
and eyebrows; adermatoglyphia, hyperkeratosis of palms and
soles; mucosal leukoplakia (75%); and dystrophic nails (85%)
(After 5 years of age).
 Conjunctiva, lacrimal duct, esophagus, urethra, vagina, and anus,
can be involved, sometimes with stenosis and, for example,
dysphagia or dysuria.
 Pulmonary vascular involvement.
 Aplastic anemia -In late childhood or early adulthood
 Secondary malignancies.
DIAGNOSIS
 Phenotypic findings.

 Cytopenias on hemogram

 Genetic analysis for telomerase complex gene mutations.

 Shortened telomere length in leukocytes also can be assessed by

fluorescence in situ hybridization studies.
TREATMENT AND PROGNOSIS
 Transplantation might improve the cytopenias but not the
abnormalities of other organs or the frequency of secondary non-
hematopoietic cancer.
 Median survival is about 30 years.
 Incidence of squamous cell carcinoma of mucosal sites is
increased, often originate in sites of leukoplakia in the skin,
gastrointestinal, or genitourinary tracts.
 Mortality from neutropenic infection or thrombocytopenic
hemorrhage - two-thirds of patients with aplastic anemia.
SHWACHMAN DIAMOND
SYNDROME
 Once in every 100,000 births.
 Exocrine pancreatic insufficiency with secondary steatorrhea.
 Blood cell deficiencies.
 Skeletal abnormalities.
PATHOGENESIS
 Shwachman-Diamond syndrome results from mutations in the
SBDS gene on chromosome 7q11, which induces accelerated
cellular apoptosis via the FAS pathway.
CLINICAL FEATURES
 Pancreatic insufficiency, steatorrhea, and neutropenia at diagnosis
in most of the patients.
 Neutropenia -95%
 Anemia -50 %
 Thrombocytopenia-35 % of patients.
 Steatorhea- nutritional inadequacies and failure to thrive.
 Skeletal abnormalities- Osteopenia, syndactyly, supernumerary
metatarsals, coxa vera deformity, dental enamel defects and
caries.

 Delayed puberty is common.

 Pancreatic cell lipase production improves with age, and around

half the patients have improvement in lipid absorption in the small
bowel with time.

 Mortality is due to overwhelming sepsis.

LAB INVESTIGATIONS
 Sweat chloride
 Serum trypsinogen
 Isoamylase levels
 Fecal fat measurement
 Fat soluble vitamin levels
 Skeletal imaging studies
 Cytogenetic abnormalities involving chromosomes 7 and 20 in
marrow cells.

 A significant risk of progression to a myelodysplastic syndrome

or acute myelogenous leukemia.
TREATMENT
 Supplemental pancreatic enzymes, to provide proper nutrition.
 Appropriate and prompt treatment of bacterial infections with
antibiotics is important.
 Prognosis depends on severity of the cytopenias.
 If symptomatic pancytopenia, especially neutropenia, is present,
median survival is about 20 to 30 years. If mild, survival is upto
the fourth or fifth decade of life.
CONGENITAL AMEGAKARYOCYTIC
THROMBOCYTOPENIA
 M=F, age of presentation:- 0-5 years.
 Genetics:- AR (biallelic mutations in the Thrombopoietin receptor
c-Mpl , at 1p34)
 Raised serum Thrombopoietin levels.
 C/F :- petechiae
 Lab:-
 Thrombocytopenia
 Decreased megakaryocytes in marrow
 Risk of aplastic anaemia, MDS , leukemia
THROMBOCYTOPENIA ABSENT
RADII ( TAR)
 Genetics:- AR
 C/F :- Absent Radii

with thumbs present

 Lab:- Thrombocytopenia (usually

improves with age).

 Decreased megakaryocytes in marrow.
 Risk of AML.
 Diagnostic test:- Arm X- ray
PURE RED CELL APLASIA
CELLULAR RATIOS:

 Normal myeloid to
erythroid ratio
 Ratios based on a count of 200-500
cells can provide useful qualitative  3 months-4.9
information.  1 year-4.8
 18 month-5
 The Myeloid: Erythroid ratio has been  2-6 year-5.8
widely used and is the ratio of  2-9year-5.3
neutrophil and neutrophil precursor  20-29 year-3-3.38
cells to erythroid precursors.
BONE MARROW
PATHOLOGY, THIRD EDITION, BARBARA J. BAIN
CLONAL HEMOPOIESIS
PLURIPOTENT STEM CELL

MULTIPLICATION COMMITTMENT

COMMITTED
STEM CELL STEM CELL
MULTIPLICATION
COMMITTED
STEM CELL
PROGENITOR
CELL;bfu-e

CFU: e COLONY
FORMING UNIT

PROERYTHROBLAST
 PURE RED CELL APLASIA
Pure red cell aplasia (PRCA) is a syndrome characterized by
 Normochromic normocytic anemia,
 Reticulocytopenia (reticulocyte count <1%)
 Almost a complete absence of erythroblasts from the bone marrow
(erythroblasts <0.5%)
TERMINOLOGY
 PRCA is used to describe this disorder in adults.
 Diamond-Blackfan anemia (DBA) used for the congenital, commonly
in infants.
 Transient erythroblastopenia of childhood (TEC) used for acquired
forms, occur in children.

DBA can present in adulthood and should be considered in the

differential diagnosis of PRCA at any age
CLASSIFICATION OF PURE RED CELL
APLASIA

PRCA

CONGENITAL ACQUIRED

NON-
INHERITED INHERITED PRIMARY SECONDARY
CONGENITAL PRCA

NON
INHERITE
INHERITE
D
D
DIAMOND
PEARSON
-
SYNDROM
BLACKFA
E
N ANEMIA
ACQUIRED PRCA
Primary Secondary -
 Autoimmune (includes TEC)  Thymoma
 Preleukemic  Hematologic malignancies
 Idiopathic  Solid tumors
 Infections
 Chronic hemolytic anemias
 Collagen vascular diseases
 Drugs and chemicals
 Pregnancy
 Severe renal failure
 Severe nutritional deficiencies
 Miscellaneous
DIAMOND-BLACKFAN ANEMIA

 First recognized as a discrete clinical entity in 1938

 One of a rare group of genetic disorders known as the inherited bone
marrow failure syndromes (IBMFS)
 These disorders share
 Predilection to bone marrow failure
 Birth defects
 Cancer
 Characterized by proapoptotic hematopoiesis.

IBMFS have provided extraordinary insights into DNA repair, telomerase function, the
misfolded protein response, signal transduction, and, in the case of DBA, ribosome
biosynthesis.
 Classical diagnostic criteria are

1.Normochromic, usually macrocytic and occasionally normocytic

anemia, developing in early childhood
2.Marked reticulocytopenia
3.Normocellular bone marrow with selective deficiency of erythroid
precursors
4.Normal or only slightly decreased granulocyte count
5.Normal or slightly increased platelet count.

(Many nonclassical cases exist)

 Diagnostic criteria
Age less than 1 year
Macrocytic anaemia with no other significant cytopenias
Reticulocytopenia
Normal marrow cellularity with a paucity of erythroid precursors

Supporting criteria
• Major
Gene mutation described in ‘‘classical’’ DBA
Positive family history
• Minor
Elevated erythrocyte adenosine deaminase activity
Congenital anomalies described in ‘‘classical’’ DBA
Elevated HbF
No evidence of another inherited bone marrow failure syndrome

British Journal of Haematology, 2008 ,142, 859–876

GENETICS AND INHERITANCE
 40–45% of DBA cases are familial with autosomal dominant inheritance
(Orfali et al,2004)

 55-65% being sporadic or familial with seemingly different patterns of

inheritance.

 Unpredictable transmission with examples of reduced penetrance and co-

existence of both mild and severe forms within a pedigree (variable
expressivity) (Gustavsson et al, 1997; Willig et al,1999a,b; Gripp et al, 2001).

 Indeed up to 30% of these families were identified from family studies on

‘‘sporadic’’ patients (Orfali et al, 2004).
 25% of sporadic and inherited cases mutations are seen in a gene (DBA1)
for RPS19, mapped to chromosome 19q13. Thus genes remain to be
discovered in almost 75% of patients.

 Current evidence strongly supports that in patients with RPS19 mutations,

DBA results from RPS19 protein haploinsufficiency.

 A second gene coding for RPS24, and a third, for RPS17, and the
likelihood that other ribosomal protein genes are mutated in DBA

 It has become widely accepted that DBA is a disorder of ribosome

biosynthesis

 Results in an intrinsic progenitor defect that involves its inability to

respond normally to inducer(s) of erythroid proliferation and
differentiation thereby accelerating apoptosis
 Normal and DBA erythropoiesis.

Johan Flygare, and Stefan Karlsson Blood 2007;109:3152-

3154
 The ribosome and RPS19.

Johan Flygare, and Stefan Karlsson Blood 2007;109:3152-

3154

©2007 by American Society of Hematology

 Principal cleavage sites

matologica |Diamond-Blackfan anemia: a ribosomal puzzle, 2008; 93(11) | 1603

CLINICAL PRESENTATION
 Presents in infancy.

 Severe anemia at birth in 25% of patients

 65% diagnosed by 6 months of age and 90% within the first year of life

 The disease may also present in older children and adults

 Incidence in males equals that in females.

 An unusually high proportion of mothers of patients have a prior history

of fetal loss, either miscarriages or still births.
 ASSOCIATED PHYSICAL
ABNORMALITIES
 Low birth weight
 Short stature, no steroid
CLEFT PALATE
 Head and face:
“Cathie” facies
Other facies
“CATHIE FACIES” Small head
A pattern of facial features
which includes a short nose
with a
Large head
broad nasal bridge (the upper 
part of the nose), widely- Jaw and mouth
spaced
eyes, and a thick upper lip;
Small jaw alone
MICROTIA Small jaw plus cleft palate
(Pierre-Robin syndrome)
Cleft palate alone
Cleft palate and lip
 Flat nasal bridge
 Abnormal ears
 Abnormal eyes:
Hypertelorism
Epicanthal folds
Ptosis
Strabismus
Blue sclerae Typical displaced and “trigger”
Congenital cataracts thumbs in a patient with
Microphthalmia Diamond-Blackfan anemia
Glaucoma
 Neck:
Short
Webbed

 Thumb:
Triphalangeal
Duplicated or bifid
Subluxed
Hypoplastic
 Renal:Dysplastic,
Absent
Horseshoe
Duplicated ureters
Caliectasis

 Congenital heart disease:

Ventricular septal defect
Atrial septal defect
Coarctation of aorta
 Other:
Mental retardation
Hypogonadism
Asplenia
DIFFERENTIAL DIAGNOSIS
 Anemia of hemolytic disease of the newborn .

 The inherited bone marrow failure syndromes .

 Aplastic anemic crises.

 Transient erythroblastopenia of childhood.

 Acquired causes.
LABORATORY FINDINGS
HEMOGRAM:

 The degree of anemia is highly variable at diagnosis and erythrocytes

may be macrocytic or normocytic.

 MCV is elevated & Reticulocytopenia is profound.

 Platelets are normal or elevated.

 Leukocytes may be normal or slightly decreased at presentation

 Neutrophils often decline with age, and in adult survivors neutropenia

occasionally is severe.
BONE MAROW
 Bone marrow biopsy and aspirate usually reveals normal
cellularity with a paucity of erythroid precursors.

 Myeloid and megakaryocyte lineages appear normal.

 Myeloid-to-erythroid (M:E) ratios at diagnosis are usually around

10:1 and with time may become as high as 100:1

 This progression of erythroid failure (with time) seems to parallel

the more severe abnormalities in in vitro progenitor differentiation
observed in older chronically affected patients as compared to
those newly diagnosed
 IRON STUDIES:
Serum iron, total iron-binding capacity, serum transferrin and serum
ferritin

 Vitamin B12 and folate are elevated or normal .

 Erythropoietin levels seem to reflect the degree of anemia or may be

elevated for the degree of anemia and remain elevated even in steroid-
responsive patients.
 Persistence of “fetal-like” red cells, with macrocytosis

 “i” antigen, increased fetal hemoglobin (HbF), and red cell glycolytic
and hexose-monophosphate (HMP) shunt enzyme activities
characteristic of fetal cells, are a consistent finding

 The vast majority of DBA patients have a normal karyotype

TREATMENT

STEROIDS

RED CELL
TRANSFUSION +
CHELATION

HSCT
PROGNOSIS
 Median survival is probably >40 yr of age, although definitive data are
lacking.

 Spontaneous remissions are seen in ~20%, and most occur in the first
decade.

 Corticosteroid therapy is beneficial in ¾ of patients who respond

initially. About ½ of patients are long-term responders.

 Due to the complications of chronic transfusions prevention and

treatment of iron overload should be aggressive.

 Acute leukemia (usually myeloid) and myelodysplasia occur in a <5%

of patients.
THANK YOU