6. FBC Indices
HGB
3.4g/dl
(11-16)
Indices Values Range for 1 month
MCV 93 88-115
MCH 29.8 33-39
MCHC 31.9 28-36
RDW 19.0 14.6-16.4
RBC 1.01 4.6-6.7
Interpretation: Normocytic hypochromic anemia
7. Other Indices in FBC
WBC
4.3 x 103 U/L
(5-20)
Differential Values Normal Range
ABN
2.4 x 103
U/L
1.0-7.0
ABL 1.3 x 103
U/L
4.0-10.0
Platelet 157,000 x 103 U/L 150-350
Final Interpretation: Pancytopenia
8. What Blood test we can do now
to know Marrow function?
RETIC COUNT
10. • Workup of pancytopenia
Provisional Diagnosis
• Fever and Pancytopenia
? Bone Marrow Suppression
Admitted to the ward:
• For PRBC transfusion
11. Extended History Birth History:
36/52 , NVD, SKH UAQ
Mother had fever several times during pregnancy treated with antibiotics prior to delivery
Baby was found to be , and was
given PRBC transfusion
Vaccination: Took HBV and BCG at birth
Feeding: Aptamil formula feed
Developmental history: Age-Appropriate
Family history:
Born to Healthy consanguineous parents
Younger of two siblings
Elder sibling is healthy
12. Summary :
1.5 months boy
Ex-Preterm 36/52
Fever and URTI symptoms 2 days
Pallor
Anemic at birth
Mother had antenatal fever several times
Non-contributory family history
CBC
• WBC: 4.3
• HGB: 3.4
• PLT:157,000
• Corrected
Retic. Count:
0.5%
16. Initial management :
Spiking fever
Baby was irritable, crying
Vitally stable
What management at this point ?
• LP was done
• IV Ampicillin & Gentamycin
21. Is coagulation profile normal/ is there
a bleed?
• Test Organ function
• Look for areas in which he might Bleed
DAY 1
22. Organ Function :
Tests Result Range
Liver Function Tests
ALAT 19 0-56
ALP <449267
Albumin 3.2 3.8-5.4
Coagulation Studies
PT 15.6 11.5-15.3
43.8 35.1-46.3PTT
1.3 0.86-1.22INR
Fibrinogen 279 200-400
Stool Occult Blood Negative
DAY 1
30. TORCH Screen
Organism Result
TOXO IgM Negative
Rubella IgM Negative
CMV IgM &
DNA PCR
Negative
HSV-1 &2 IgM Negative
Blood Virology Studies
Organism Result
ParvoVirus IgM &
DNA PCR
Negative
EBV IgM Negative
HBsAg Negative
HCV IgM Negative
HIV Ag/Ab
Negative
Respiratory Viral Screen
• Enterovirus
31. Enteroviral Infection
Enterovirus is a relatively uncommon cause of pancytopenia
Respiratory viral agents if cause bicytopenia its mostly low
wbc, and low plts, not common to see anemia
Cytopenia was shown to resolve over a week after the onset of
symptoms
HK J Pediatr (new series) 2017;22:10-13
32. Serial FBCs during admission
FBC
Values
Day1 Day2 Day3
WBC
ABN
4.3
2.9
4.7
2.4
4.1
0.6
ABL 1.3 1.3 3.0
HGB 3.2 8.2 8.2
PLT 157 129 121
34. Drugs / Toxins:
NO history of Drug intake or toxin exposure:
Anti-epileptics: Phenobarbitone
Anti-thyroid: Prophythiouracil
Chloramphenicol
Lindane (benzene)
Heavy metals Arsenic
DAY 1
36. What am I looking for
• Blast Cellsleukemia
• Tear drop cellmyelofibrosis
• Reactive lymphocytesEBV
37. Blood Film:
RBC: Severe Normocytic anemia, few schistocytes, irregular
contracted cells,
WBC: Mild Leucopenia, No immature cells Seen
PLT: No comments (perhaps it was normal)
DAY 2
40. Bone marrow Aspiration Done
What to expect?
Bone Marrow Finding DIseases
Hypocellular
• Aplastic Anemia
Hypercellular
• Acute Leukemia
• Overwhelming infection
• SLE
Infiltration
• HLH
• Storage Disease
41. Bone Marrow Aspiration Findings
• NormalCellularity:
• Normal and orderly maturationGranulopoietic cells
• Normal Morphology and plentifulMegakaryocytes:
• Normal Morphology and numberLymphocytes:
• Moderate megaloblastic changes and
Dyserythropoiesis
Erythroid series:
• NO sideroblastsIron stain
Other features:
42. Bone Marrow Aspiration Findings
Conclusion :
Megaloblastic changes in Erythroid line with moderate
dysplasia
Suggested Diagnosis:
Congenital Dyserythropoietic anemia
Congenital Sideroblastic anemia
Fanconi Anemia
Further Action:
Do Bone Marrow biopsy
43. Considered the Suggested Diseases
Conditions
Hepato-
splenomegaly
Hemolysis
Jaundice
Retic Count Bone Marrow
Our patient nil Nil Low
Erythroid
dysplasia,
megaloblast
Congenital
Dyserythropoeitc
Anemia
present present High
Erythroid
dysplasia,
megaloblast
Congenital
Sideroblastic
Anemia
- - Normal
PAS+,
Ringed
sideroblast
48. Storage Disease as a cause of Pancytopenia
Disease Gaucher Nieman Pick Patient
Age
Early childhood
Can present in 1st year
Infancy adulthood
Can present in Infancy Birth
Liver function Hepatosplenomegaly
Hepatosplenomegaly,
liver failure Nil
Neurologic function
Variable neurologic
impairment
Gross motor
developmental delay normal
Other Labs Raised LFT
High lipids
Raised LFTs normal
Bone Marrow Findings Gaucher cells Foam Cells No such cells
49. Sent for Karyotyping and
Chromosomal Breakage study
DEB : NEGATIVE
KARYOTYPE: 46XY
DAY 4
53. B and T lymphocytes
Lymphocytes CD markers Values Range
B lymphocytes
CD 19 0.6% 5-20.0
LOW
CD 20 0.7% 4.00-19.0
T- Lymphocytes
CD 3 96.7% 59-85
NormalCD 4 78.6% 31-55
CD 8 15.6% 17-38
NK cells CD56 54 Normal
DAY 4
55. Course During the Admission
Fever improved in 2-3 days
Remained clinically and vitally stable
Discharged with follow up in Hematology clinic
Discharge Diagnosis:
Pancytopenia
B cell Immune deficiency
DAY 5
57. Follow-Up FBC in clinic
FBC
Values
7th FEB 17 26th FEB 17 30th MAR 17
WBC
ABN
3.5
0.5
3.7
1.2
4.3
1.0
ABL 2.3 2.1 2.8
HGB 7.3 6.6 8.0
PLT 163 102 150
58. Follow up Lymphocyte level
Lymphocytes CD markers
Values Values Values
2nd FEB 17 8th FEB 17 22nd FEB 17
B lymphocytes
CD 19 0.6% 0.6% 0.8%
CD 20 0.7% 0.7% 0.8%
T- Lymphocytes
CD 3 96.7% 94.5% 94.0%
CD 4 78.6% 73.8% 74%
CD 8 15.6% 16.2% 17.0%
NK cells CD56 54 63 63
62. On return from Germany:
Repeated tests:
• Bone Marrow Aspirate:
Cytopenia of three lineages
• Genome sequencing:
MYSM1 Mutation
63. MYSM1 Mutation
Other Cases:
There have been cases cited where MYSM1 mutation has resulted in
pancytopenia from birth requiring Bone Marrow transplant.
Experiments:
Knock out Mice where removal of MYSM1 gene has resulted in severe
pancytopenia and B cell immunodeficiency
A Human Bone Marrow Failure Syndrome Caused By a Homozygous Mutation
in MYSM1, Blood 2015 126:1204;
Control of B Cell Development by the MYSM1, Immunity. 2011 Dec 23; 35(6): 883–896.
64. SUPPORTIVE CARE:
For transfusion of PRBC
To give him immunoglobulin's about every three weeks
To start on G-CSF
He had required few admissions after travel for fever
and neutropenia
Plan:
65. His bone marrow function will continue to decline
Bone marrow transplantation will be needed to cure
him from his disease
HLA typing with his siblings , it has been fully matched with
his sister
Prognosis:
66. Thank YOU !
TO OVERCOME EVIL WITH GOOD IS GOOD, TO RESIST EVIL BY EVIL IS EVIL.
MUHAMMAD (PBUH)
Editor's Notes
We have a boy who 1.5 months when admitted.
Fever: low grade
Cough and runny nose:
Normal review of system
Growth parameters:
Height: 53cm- 50th
Weight:3.96kg – 50th
Head circumference: 34.5cm -10th
Healthy consanguineous parents, 1st cousins. He has an elder sibling 2.5 years who is healthy as well. No family history of anemia or blood disorder.
Life span of transfused RBCs is 50-60 days
Reports not available
Anemic At Birth requiring transfusion ? No perinatal bleed
Acquired causes: 70%
Congenital 30%
Infection:
Idiopathic – 80 percent
●Post-hepatitis – 9 percent
●Post-viral infection – 7 percent
●Drugs, other toxins – 4 percent
Intrinsic: Congenital /inherited: genetic disorders with pancytopenia as one of the manifestations
Initial battery of labs were collected including limited septic workup blood and urine.
Markers for infection / inflammation,
70ml over 4 hours
Malignancy/infiltrative bone marrow diseases : ALL, AML
To Examine for Blast cells in Peripheral Blood and clues to other causes of pancytopenia
Blood film will take time, so until results comes back, lets see what other tests can be sent at this time
May reveal enlarged medistinial shadows ( thymoma and metastatic infiltrations , leukemias)
His platelet count is low , and pancytopenic, if coagulation system is disturbed he may or even may be bleeding
Or Coagulation Defect leading that resulted in bleeding
We must do Coagulation profile and look for body organs that
Brain(Disturbed consciousness, USS brain) , Chest (CXR, Respiratory distress), Abdomen( distention , USS Abdomen) , Thigh (obvious)
Liver enzymes are elevated in many viral induced pancytopenia which isn’t the case
No liver dysfunction
Normal coagulation studies
NO factors which would predispose him to bleed
Causes : Acquired: 70% pancytopenia
The test we do will represent the differential diagnosis we want to RULE OUT
Culture take 12-24h hours to release report
Traumatic, rbcs are high but wbcs normal
CSF WBC Correction in Blood Contaminated CSF: it to be insignificant
CSF: rbc’s? traumatic
Enterovirus is a relatively uncommon cause of pancytopenia
Moreover respiratory viral agents if cause bicytopenia its mostly low wbc, and low plts, not common to see anemia
Cytopenia was shown to resolve median 12 days (7-28) after the onset of symptoms
references
Circle: blood transfusion given
5 days of symptoms
Arsenic (contaminated water source)
MDS: Nucleated RBCs, Bilobed neutrophils, Giant platelets, Acanthocytes
Myelofibrosis: Dacrocytes, normoblasts erythrocyte, immature granulocyte
Leukemia
ALL: Lymphoblast
AML: Anisopoikilocytosis ? , large platelets
Blasts are cells that have a large nucleus, immature chromatin, a prominent nucleolus, scant cytoplasm and few or no cytoplasmic granule
Reactive: nucleus is coarse, deep blue and can have rather plenty of cytoplam
Leukemia
Hematophagocytic Lymphohistiocytosis
Myelofibrosis
Myelodysplasia
Schistocytes may be artefacts, but is reported only when it is >1% ( significant) can normally be seen in neonates, with infection , for it be significant it should correlate with other features such findings of hemolysis , uremia
There is no hard and fast rule towards proceeding to Bone Marrow Biopsy, You may rule out inherited pancytopenia if there are pathognomic physical features , BMA may be done while considering IP, As most of the inherited pancytopenias would required BMA as a workup study
Hypocellular: Aplastic anemia which can be because of Inherited or acquired depending on history and PE
Hypercellular: Acute leukemia Blast cells ; lymphoblast for ALL and myeloblast for AML
Non- specific hypercellularity without blasts cell in case of peripheral destruction which is in case of overwhelming infection periphraly, SLE, Evans Syndrome
Infiltration: Gaucher cells, Foam cells, hematophagocytes
Normal Cellular: it may not be normal because there are less peripherally , it should be atleast hypercellular to indicate it is working normally
Leukocyte, Platelet, Lymphocyte: normal in morphology
Erythrocyte: Dysplastic megaloblastic
Normal M?E ratio is 2:1 to 4:1, in case of infection it increases to 6:1, and leukemia 25:1
Hematogones are benign lymphoid progenitor cells in pediatric especially preterm infants
Normal M?E ratio is 2:1 to 4:1, in case of infection it increases to 6:1, and leukemia 25:1
No Aplasia, No leukemia, No MDS, No Metastasis, No HLH
CDA: fragile RBCs destroyed peripherally hepatosplenomegaly , High Retic count
FA: chromosomal fragility test
Causes : Acquired: 70% pancytopenia
FA: Facies : Microcephaly , small eyes, other : thumb anamolies, Hyperpigmented intertrginious areas
SDS: thorax dystrophy
CAMT: Anamolies of face,feet, cerebral atrophy
DC: Reticular pigmentation of skin, nail dystrophy
Gene: SBDS gene, DKC-1, MPL gene
Certain Aneuploidies are more prone to Pancytopenias
Trisomy 8 syndrome – warkany syndrome
NIEMAN PICK: A and B and C, : primary deficiency of acid sphingomyelinase activity accumulation of sphingomelin
Age: early childhood to late adulthood in type C
Hepatosplenomegaly ( not universal) Lipids: Increased LDL reduced cholesterol and HDL
Nieman Pick findings: Excessive sphingomyelin with, Foam Cells
Gaucher Disease: leads to accumulation of glucocerebroside in various organs including bonemarrow absence of glucocerebrosidase
Liver: almostall types have hepatosplenomegaly
Neurologic; Mental retardation , seizures, ocular abnormalities
Gaucher Cells: Large blue round cells wrinkled appearance
Causes : Acquired: 70% pancytopenia
We had done a flow cytometric Analysis with the bone marrow study
Flow cytometry done along with bone marrow aspiration
As part of the screening for low WBC count , B and T lymphocyte was sent, can we send immunogloulins at this stage no as the baby is still too small and have maternal immunoglobulin which start weaning off by 2 – 6 months
A unique combination, was not found to be part of any textbook syndromes
Viral suppression or intrinsic pancytopenia
Follow up was done over several weeks and he persisted to have pancytopenia , giving clue that the cause is rather persistent and possibly intrinsic bone marrow.
At these stages he required irradiated blood transfusion given approximately 4 times
The serial B lymphocyte levels persisted to be low confirming the initial result, and that it isn’t of transient nature.
Initially low immunoglobulins confirmed on repeat evaluation of study 2 & 3 months of age and they were consistent with b – lymphocyte deficiency
We did Literature search for novel combination and found it is extremely unique and the closest similar case is: SIFD
And still it was similar in the Presentation Of severe congenital anemia , B cell immunodeficiency B-cell lymphopenia and panhypogammaglobulinemia
but dissimilar in many other context : neurologic degenerative features: Seizures, developmental delay or periodic fever (without infective cause)
They repeated similar tests and repeated bone marrow where the found hypocellular bone marrow. No other test was confirmatory. They did genomic testing which should a rather novel mutation.5 months
Bone marrow:
most prominent in the erythroid precursors but also the white blood cells and a little in megakaryopoiesis
MYSM1 short for Myb-like, SWIRM, and MPN domains-containing protein 1” gene Hematopoiesis
In Germany tests were repeated which were inconclusive they repeated Bone marrow and performed complete genomic sequencing
Homozygous,
Plan was devised in association with Doctors in Germany that he would need supportive care in the mean while:
For transfusion of PRBC, Irradiated, leukoreduced,
Immunoglobulin infusion depencing on his IgG Levels
IVIG: depending on his IgG-levels
Filgrastim: if his neutrophil leukocytes are below 500/µl. G-CSF is a growth factor for neutrophil granulocytes which are important for preventing bacterial infections.
He had required few admissions after travel for fever and neutropenia but remained stable and non of them were severe due to supportive care
HSCT: It was concluded that his bone marrow function will continue to decline, and that he would need a “new” healthy bone marrow, to cure him from the disease
Currently he has done HLA typing with his siblings , it has been fully matched with his sister, he is already being prepared for possible BMT in USA