Pancytopenia
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1) A 1.5 month boy presented with fever and pancytopenia. Examination found pallor. Blood tests found normocytic anemia, leukopenia, thrombocytopenia. 2) Bone marrow aspiration found erythroid dysplasia and megaloblastosis. Chromosomal breakage study and karyotyping were normal. 3) Flow cytometry found B cell immune deficiency. The pancytopenia and symptoms improved with supportive care. 4) Genetic testing in Germany found a MYSM1 mutation, which has been associated with bone marrow failure and immunodeficiency. The patient will require long term supportive care including transfusions, immunoglobulins and G
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Pancytopenia
- 1. Case presentation PEDIATRIC HEMATOLOGY Dr. Fahad Pediatric Resident PANCYTOPENIA
- 2. Case 1.5 month boy, Corrected 2weeks, 36/52, has been brought to the ED Fever Cough Runny nose 2 days
- 3. Examination General Condition: Pale NO apparent dysmorphism NO lymphadenopathy NO jaundice Mild puffy face Well hydrated Capillary refill <2 sec Non-sick looking Vitals: HR: 189 /min Spo2: 98% BP: 102/50 RR: 66/min Temp: 37 C
- 4. Systemic Examination Systemic Exam: Chest: Bilaterally equal air entry , no adventitious sounds CVS: S1+S2 no murmur heard, pulses well felt and equal, GIT: Soft, Non distended, no organomegaly CNS: Ant. Fontaelle soft, Neonatal reflexes intact ENT: Congested throat , normal ears Skin: No rashes Eyes: No icterus , normal
- 5. What Lab test to send? FBC
- 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
- 9. Retic Count: Retic Count: 2.3% Corrected Retic Count: 0.5% Range: 0.6-1.1%
- 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%
- 14. 1st : Acquired Pancytopenia Infection Drugs/Toxins Malignancy Infiltrative diseases Inherited Pancytopenia Bone Marrow Failure Syndromes Storage diseases
- 15. Initial management : Admitted to ward 3 reverse isolation Initial Labs were collected PRBC transfusion DAY 1
- 16. Initial management : Spiking fever Baby was irritable, crying Vitally stable What management at this point ? • LP was done • IV Ampicillin & Gentamycin
- 18. What first to do ? DAY 1 To Rule out the most serious Cause
- 19. Blood Film DAY 1
- 20. CXR RESULT: NORMAL HEART AND LUNG SHADOW DAY 1
- 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
- 23. Bleeding: Radioimaging Result USS Brain Normal USS Abdomen Normal , No Organomegaly
- 24. What Other Tests to Do? DAY 1
- 25. General algorithm: CBC Blood film Bone Marrow Aspiration/biopsy Acquired Inherited Retic. Count
- 26. Is it sepsis or Viral Induced? DAY 1
- 27. Infection: Sepsis Screen Result Reference CRP 6520 mg/ml <5 Procalcitonin 0.19 0.05-0.49 (low risk) Cultures Urine No growth - Blood No growth -
- 28. Infection: CSF Labs Values Range WBC <5 <5 RBC 200 NIL Protein 75 20-72 Glucose 53 32-82 Chloride 124 118-132 Culture No growth - DAY 1
- 29. Infection: Labs Values Reference Urine WBC 2-3 NIL RBC 0-1 NIL Protein NIl NIL
- 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
- 33. Is it Drugs/Toxins? DAY 1
- 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
- 35. Blood film is ready DAY 2
- 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
- 38. General algorithm: CBC Blood film Bone Marrow Aspiration/biopsy Acquired Inherited Retic. Count
- 39. No definitive answer ? BONE MARROW ASPIRATION DAY 3 AND FLOW CYTOMETRY
- 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
- 44. General algorithm: CBC Blood film Bone Marrow Aspiration/biopsy Acquired Inherited Retic. Count
- 46. Conditions Schwacman Diamond Syndrome Fanconi Anemia CAMT** Dyskeratosis Congenita Patient Family history AR AR AR any Nil Age 1y 3-14y 4y 14years Birth Physical Features Anamolies Nil malabsorption --- Isolated low plt --- Bone Marrow Hypocellular cellular Diagnosis Chromosomal Breakage study (Fanconi Anemia) Gene testing - **Congenital Amegarkyocytic Thrmobocytopenia
- 47. Aneuploidy Monosomy 7 Syndrome Trisomy 8 Trisomy 21 – Down Syndrome
- 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
- 50. General algorithm: CBC Blood film Bone Marrow Aspiration/biopsy Acquired Inherited Retic. Count
- 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
- 54. Findings: • Pancytopenia • B cell Immune deficiency
- 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
- 56. Follow-up
- 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
- 59. Immunoglobulins Immunoglobulins Values Values Range 27th FEB 17 21st MAR IGG 1.59 1.63 1.69-5.58 IGA 0.18 <0.07 0.05-0.46 IGM 0.23 0.11 0.23-0.85
- 60. Literature search Pancytopenia + B-cell immunedeficiency A novel syndrome of congenital Sideroblastic anemia, B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD) A novel syndrome of congenital sideroblastic anemia, B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD). Wiseman DH1 2013 Jul 4;122(1):112-23
- 61. Further Course Medical report was issued the parents took the baby to Germany for further workup
- 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