PANCYTOPENIA IN A CHILD
Dr Zubaidah Ahmad
31/10/18
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Question
• A 2 year old girl present with pallor, fatigue
and bruising and is found to be pancytopenic.
Outline your approach to further diagnostic
assessment in this patient, including:
• A) Differential diagnosis
• B) Relevant history/features
• C) Laboratory investigations
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Introduction
• Pancytopenia is defined as a reduction in all
three cells cellular elements of blood,ie
• Hb<10g/dl
• ANC<1.5x109/l
Severe pancytopenia:
• Platelet<100x10 /l9
Hb<7g/dl
ANC<0.5X109/L
Platelet<20x109/l
(clinical hematology in clinical practice,Blackwell)
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• Recognition of the correct diagnosis is
important as the management is different.
• Some of the conditions are treatable and
reversible (such as in megaloblastic anaemia,
infection) while some required more intensive
therapy.
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• Mechanism of pancytopenia:
• i) Bone marrow infiltration/replacement (eg
leukemia, MDS), infectious disease (miliary
TB).
• ii) Bone marrow aplasia cause by nutritional
disorder, aplastic anaemia, immune
destruction, drugs.
• iii) Blood cell destruction or sequestration. Eg
in DIC, ineffective haematopoiesis (MDS,
megaloblastic anaemia). Sequestration as a
result from hypersplenism (eg from liver
cirhosis, autoimmune disorder)
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Possible causes of pancytopenia in children
Pancytopenia
Decrease Increase
production consumption
Aplasia Infiltration Sequestration Haemophagocytic
Liver disease Syndrome
Congenital Temporal BM Acquired
suppression
Congenital
FA,SDS,DC Acute
Leukemia/other
malignancies
Acquired
Primary Secondary 6
AA, B12/folate deficiency Hepatitis ,Drugs
» Overview of common causes of pancytopenia
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Inherited bone marrow failure syndrome
(IBMFS)
• DDD
• Davies et al; An update on the management of severe idiopathic aplastic anaemia in
children, BJH
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Aplastic anaemia
» Pancytopenia with hypocellular marrow
without infiltration/fibrosis
» To diagnose AA, at least two of the following
are present:
» (i) hb<10g/dl
» (ii)plt<50x109/l
» (iii) ANC<1.5X109/L
» Idiopathic (70%-80%)
» Secondary causes eg drugs history, infections,
chemotherapy, ionising agents 9
» Modified Camitta criteria use to assess
severity:
» Severe: BM cellularity <25% (or 25%-50% if
<30% residual haemopoietic cells) and at least
2 of the following:
» ANC<0.5X109/l,
» platelet<20x109/l,
» reticulocyte count<20x109/l
» Very severe: as severe but PB ANC<0.2X109/L
» Non-severe: does not fulfil criteria for severe
and very severe.
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MDS of childhood
» Rare, account for <5% of childhood
malignancies
» >30% associated with IBMFS
» Germ line syndrome predispose to MDS and
AML eg. GATA2, ETV6,SRRP72 mutation
» Characterized by peripheral cytopenia,
dysplassia, IE, cytogentic abnormality and
tendency to develop AML.
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• Hemophagocytic lymphohistiocytosis (HLH), which
– Either primary or acquired.
– The clinical diagnosis of this syndrome requires the presence of 5 or more of
the following:
• fever,
• splenomegaly,
• cytopenia involving 2 or more cell lines,
• hypertriglyceridemia or hypofibrinogenemia,
• hepatitis,
• low or absent natural killer cell activity,
• a serum ferritin level higher than 500 μg/L,
• soluble CD25 higher than 2,400 U/mL,
• hemophagocytosis as demonstrated in bone marrow, spleen, or lymph node.
– primary familial occurs most often in infants younger than 1 year, and has
been found to be the result of uncontrolled T-cell and histiocyte activation.
– Mutations in several proteins, including perforin 1, UNC13D, and syntaxin 11,
have been implicated in this disease.
– syndrome is most often triggered by a stimulus, such as infection, and
numerous viruses, bacteria, and parasites have been implicated
» Drugs: dt direct cytotoxic effect or immune
mediated.
» Eg. Allopurinol, antibiotic (chloramphenicol,
bacterium), benzene, anticonvulsant (eg.
carbamazipine), NSAID
» Infections: HIV, viral hepatitis,EBV, CMV,
parvovirus b19, TB, filariasis
» Nutritional deficiency- B12/folate deficiency
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B)Relevant clinical history/features
» History
» duration of symptoms (chronic/acute)
» Assessment of severity of pancytopenia- bleeding
tendency, recurrent infection
» Other associated symptom eg weight loss-?underlying
malignancy, joint pain/rash-?CTD,
diarrhea/malabsortion-?SDS
» Underlying medical condition/failure to thrive
» Family history of similar condition? Consanguinity? Sex
linked disease among family member- indicate
congenital condition
» Drugs history
» Dietary history
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Clinical assessment
» Dysmorphism, short stature, skin
pigmentation, reticular rash, oral leukoplakia,
nail dystrophy
» Lymphadenopathy-underlying malignancy
» Hepatosplenomegaly- if presence unlikely AA
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Aplastic anemia and clonal evolution: germ line and somatic genetics, Akiko
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Shimamura, Hematology 2016:74-82
C) Laboratory investigations
» Baseline investigation
» Test to detect an associated abnormal clone
» Test to exclude inherited bone marrow failure
syndrome
» Emerging diagnostic tests
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[Link] laboratory tests
» FBC
» Repeat to exclude spurious counts
» MCV: raised MCV -?vitB12/folate deficiency
» Reticulocyte count- reflect BM productivity
(eg. Raised count may indicate peripheral
consumption rather than aplastic anaemia)
» Differential count assessment:
Monocytopenia (GATA2 mutation)
» Criteria for aplastic anaemia (for diagnosis
and diagnostic criteria) 18
» Peripheral blood count
» Important to identify the cause of
pancytopenia
» Eg. AA- pancytopenia, no
dysplasia,dysplasia, no blast
» Leucoerythroblastic picture-?MDS, leukemia
» Presence of dysplastic features would likely
indicate presence of myelodysplasia.
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» Bone marrow examination
» Important to exclude other differential of hypo
cellular marrow apart from AA
» Can be perform with out platelet support ( BCSH
guideline,2016)
» AA: hypo cellular with prominent fat spaces and
variable no of residual haemopoietic cells. Increased
inflammatory cells.
» MDS: blasts, dysplastic features
» Trephine biopsy feature like replacement of marrow
space by blast cells in acute leukaemia,leukaemia, or
infiltration of lymphoma cells (paratrabeculae or
diffuse pattern)
» Haemophagocytosis features
» Reticulin stain:increased staining are not seen in AA.
May indicate hypo plastic MDS/evolution to
leukaemia, or BM infiltration.
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Further investigations
» Base on findings from baseline investigations
» Flowcytometry: lineage confirmation of
abnormal cells/blasts
» Cytogenetic:
» Abnormalities in acute leukaemia and MDS
(eg Monosomy 7 may indicate the
likelihood of MDS in children)
» AA: del (13q), trisomy 8 (in 12%)
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» Test to exclude
DEB (diepoxybutane) an IBMFS
test : increased
chromosomal breakage after exposure to DEB.
» PB telomere length: flow FISH or multiplex
qPCR analysis. Very short telomere
(<1percentile for age) are indicative of DC.
Telomere gene mutation analysis then
indicated (TERC,TERT,DKC1)
» Other IBMFS: specific gene mutation when
suspected. Eg SBDS for Schwachmann-
Diamond syndrome, GATA2 for Emberger’s
syndrome.
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Emerging diagnostic tests
» Molecular: eg underlying genetic abnormality
facilitating diagnosis eg. mutated C-MPL in CAMT
» PB MDS mutation panel: NGS technology to
detect somatic mutation which may help distinguish
AA from hypocellular MDS/AML
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Other investigations
» Infective screen-HIV, hepatitis B,C, EBV,CMV
» HbF level (pretransfusion sample): important
for prognostic factor in children.
» Biochemical test: Liver function test
» Sr folate and Vit B12 level
» HLA typing of siblings/ family study
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