Pediatric Board Review CoursePediatric Hematology/Oncology
Kusum Viswanathan, MDVice Chair, Dept of Pediatrics
Director, Divn of Pediatric Hematology/OncologyBrookdale Univ Hospital and Medical Center
Case 1
6 week old term infant referred for anemia. No Sx Hb 7.5, Retic 2 %, Bili 3.5, Direct 0.5. Mother O+, Baby A -, Direct Coombs + Cord blood Hb 14.2 g/dL. Bilirubin 15mg/dL at 48 hours of life, recd photo Rx and d/c at 5 days.
Most likely explanation for the anemia is
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1. G 6 PD deficiency2. Hereditary
spherocytosis3. Physiologic anemia4. ABO incompatibilty5. Rh hemolytic
disease
Newborn -anemiaHemoglobin at birth is 17 g/dl, MCV over 100.Falls to 11-12 by 6 weeks of age- nadir.Erythropoietin production shifts from liver to kidneys and reduces because of increase in PaO2.Anemia at birth could be :– hemoglobin not have equilibrated- repeat– Hemorrhage, may not have had time to mount a retic response– Acute hemorrhage- pallor and tachypnea– Look at MCV- low MCV-suggestive of
chronic feto-maternal hemorrhage Alpha Thalassemia trait.
– Kleihauer-Betke- Hb F resistance to acid elution
Newborn-ThrombocytopeniaA newborn has a completely normal physical exam except for a few petechiae. Platelet 50,000.Differential diagnosis:– Production defects:
TAR, Megakaryocytic hypoplasia, Trisomy 13, 18.Wiskott-Aldrich (small plt, X-linked, eczema , SCT cure) Infections- viral, bacterial, Infiltration (Gauchers, Niemann Pick, Leukemia)
– Destruction: Allo-immune (iso-immune)- Platelet group incompatibiltyAuto-immune: Mat ITP, Drugs (thiazide, tolbutamide), SLEInfections: CMV, Rubella, herpes, DICLoss: Kasabach- Merritt syndrome (hemangiomas, DIC- Rx DIC and hemangioma with Steroids, interferon, VCR)
The treatment of choice for alloimune neonatal thrombocytopenia is:
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1. random platelet transfusion
2. IVIG3. Steroids4. Exchange
transfusion5. Washed maternal
platelets
Immune thrombocytopeniaAuto-immune: Pregnant women with ITP/Hx of ITP – Passive transfer of antibodies (IgG) from mother. – Even when mother has a normal platelet count (Splenectomy)– Nadir-few days; Platelets < 50,00 have 1% risk of ICH.– IVIG to mother, Fetal platelet counts, C sec, US, IVGG to baby
Allo or Iso-Immune: Normal platelet count in mother– Similar to Rh disease; PL A1 antigen/ Zw a negative mother.– 97% of population is PL A 1 positive– Sensitization early in pregnancy– Plt function defect because Anti-PL A1 interferes w/aggregation.– Severe bleeding more likely; first born affected; – Recovery in 2-3 weeks– Mother’s washed (PLA1 neg) platelets; IVIG; Ultrasound;
Steroids
Kasabach- Merritt, TAR
15 months old girl presented in ER with h/o URI, and scattered petechiae and ecchymoses over the body and lower extremities. Physical exam normal, no hepatosplenomegaly. WBC-6,000, Hb 12.8, Plts-5,000, Diff: Normal Smear- The next step is to
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1. perform a bone marrow aspirate to confirm the diagnosis
2. Do a skeletal survey to rule out bony fractures
3. Start treatment with either IVIG or anti-D
4. Administer platelet transfusion
ITPUsually acute onset; immune mediated; post viralPeak 2-5 years of age, males=femalesSpontaneous bruises, petechiaePE –no lymphadenopathy (LN), hepatosplenomegaly.CBC- other cell lines normal, large plts on smearTreat if plt< 10,000 or wet ITP, avoid NSAIDS, AspirinTreat- IVIG best response, 48-72 hours; Side effects.– Anti-D (WInRho) Rh+ ,hemolysis, quick response– Steroids good response, SE, inexpensive, need BM
BM- Increased megakaryocytes, otherwise normal
Petechiae, HSP
PetechiaeITP- ThrombocytopeniaHemolytic Uremic Syndrome– Low plt ct, Hemolysis, high LDH, sick patient, Uremia,
microangiopathic hemolysis on smear.Henoch-Schonlein Purpura– Purpuric lesions on lower extremities and buttocks– Abdominal pain, arthritis. IgA deposition, normal plt ct.
ALL– Low plt ct, lymphadenopathy (LN), hepatosplenomegaly, other
cell lines affectedDrug induced- – Likely– By reducing production or increasing destruction
DIC
Platelet SizeNormal platelet 7-10 daysLarge platelets: – ITP– May Hegglin (Dohle bodies in neutrophils, Plt function normal).– Bernard Soulier syndrome (AR, Plat function disorder).
Small platelets: Wiskott Aldrich syndrome ( X-linked, recurrent infections, eczematoid rash, platelet dysfunction)
A 2 year old boy presents for evaluation of a chronic pruritic eruption. His medical history is remarkable for recurrent epistaxis, otitis media, and pneumonia. Physical examination reveals erythematous, slightly
scaling patches on the trunk and in the antecubital and popliteal fossae. Petechiae are present profusely. This is most suggestive of
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1. Acrodermatitis enteropathica
2. Ataxia telangiectasia
3. Atopic dermatitis4. Langerhans cell
histiocytosis5. Wiskott-Aldrich
syndrome
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Platelet function defects
Normal platelet numberGlanzmann thrombasthenia– AR, Abnormal aggregation– Bleeding disorder, check h/o consanguinity
Hermansky Pudlak Syndrome:– AR, Decreased dense granules– In Puerto Ricans– Oculocutaneous albinism
ThrombocytosisH- Hemorrhage, Hereditary Asplenia, Down myeloprol.I- Infections, Kawasaki, Immune:GVH, Nephrotic syndromeP- Polycythemia vera, Myeloproliferative, EssentialL- Leukemia (CML) A- Anemia,- Iron, Vit E, SideroblasticT- TumorsE- Epinephrine, SteroidsL- Lymphoma, HodgkinsE- Exercise, T- Trauma, FracturesS- Splenectomy
AnemiaAn 18 month old girl brought in for pallor. Normal diet and PMH. She is alert, interactive, only pallor, normal vital signs, No hepatosplenomegaly, lymph nodes or bruises. CBC- Normal WBC, Plt, Hb 4.5g/dl, MCV 74, Anemia– Reduced production– Increased destruction– Loss
What else do you want??
Reticulocyte count
Normal/Low- reduced production– Iron deficiency anemia- MCV will be low– ALL (leukemia)- other findings, LN, HSM– Diamond Blackfan anemia- Us < 1 year of age;
facial/thumb abn, Cong heart dis, MCV Incr, rbc ADA increased, responds to steroids, BMT curative.
– TEC: Over 1 year of age, Pallor, transient rbc production failure, recovers, MCV and Hb F high during recovery, rbc transfusion, rbc ADA normal .
Aplastic Anemia
Congenital- Fanconi anemia, Dyskeratosis congenita, Shwachman-Diamond syndrome, Amegakaryocytic thrombocytopenia– Fanconi’s anemia-AR, short stature, microcephaly, microphthalmia, epicanthal
folds, Café au lait, dangling thumbs, congenital dislocated hips. Chromosomal breakage increased by diepoxybutane (DEB) or mitomycin C. Hemorrhages, infections, leukemia, myelodysplastic syndrome, liver tumors,
Acquired Infection- hepatitis, EBV,CMV, parvovirus B19, HIVDrug induced- Chloramphenicol Exposure to Toxins, RadiationAutoimmune disease such as lupusIdiopathic
Treatment- BM/Stem cell transplant
Normal smear
Microcytic anemia is a characteristic laboratory
abnormality of all listed diseases except
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1. Iron deficiency2. Lead poisoning3. Sickle cell
disease4. Thalassemia
trait
Microcytic anemia
Iron deficiencyLow MCV, low MCHC, low retic, RDW normal initially, will increase after treatment, Low Iron, Incr TIBC, Transferrin low, Ferritin lowCauses: Inadequate dietary intake– Toddlers, too much milk, less solids, Breast fed need
iron supplements– poor absorption– Blood loss: Menstrual, GI tract, Meckels, Epistaxis
D/D: Thalassemia trait- MCV much lower in prop to anemia,Anemia of chronic disease- low Fe, low TIBC, normal /high Ferritin.
Beta Thalassemia MinorQuantitative defect in globin chains– Reduced production of Beta chains
Hb electrophoresis– Hb A- 2 Alpha, 2 Beta– Hb F- 2 Alpha, 2 Gamma– Hb A2- 2 Alpha, 2 Delta
Excess Alpha combines with Gamma or Delta- Increased Hb F and A2.Smear abnormalities significant even with MILD anemia.
AnemiaLow MCV, normal RDW, normal reticSmear shows aniso and poikulocytosis, target cells, microcytes, misshapen cells, basophilic stipplingHb Electrophoresis: Increased Hb A2 and/or F.Normal iron studies, no response to iron
Beta Thalassemia MajorNo production of Beta chainsAutosomal recessive25 % chance with each pregnancyPre-natal testing for carriersChorionic villous sampling for diagnosisTransfusion dependent-allows for normal developmentPen Prophylaxis, Anti oxidantsSplenectomy after age 5Iron overload- inherent and transfusionNeed chelators
Thalassemia- Alpha
Reduced Alpha chains4 types- carried on 4 allelles. (xx/xx)One absent- Silent carrier (x-/xx)2 absent- Alpha Thal trait (xx/- - or x-/x-)3 absent- Hb H disease (x-/- -) Has 4 excess Beta chains)4 absent- Hydrops fetalis (- -/- -)NB period: Excess Gamma chains form Hb Barts- FAST moving Hb on Newborn screening
Megaloblastic anemiasVitamin B 12 or Folate deficiency (defective DNA synthesis)Defective maturation of other cell lines- leukopenia and/or ThrombocytopeniaHypersegmented neutrophils, large metamyelocytes and bandsCauses hyperhomocysteinemia. Dietary deficiency of vitamin B12 due to vegetarianism.Can occur in breast-fed infants of vitamin B12–deficient mothersSevere vitamin B12 deficiency - a cluster of neurological symptoms in infants, including irritability, failure to thrive, apathy, anorexia, and developmental regressionUnderlying mechanisms– delayed myelination or demyelination of nerves– alteration in the S-adenosylmethionine:S-adenosylhomocysteine ratio– imbalance of neurotrophic and neurotoxic cytokines– accumulation of lactate in brain cells
Elevated methylmalonic acid and/or total homocysteine are sensitive indicators of vitamin B12–deficient diets
Case
3 year old patient is brought to the ER with complaints of feeling very tired over the past 3 days.Patient is pale, jaundiced with the spleen tip palpable.CBC Hb 5, Retic 5 %, LDH Increased,What does this sound like??
Reticulocyte count- Increased
Hemolysis– Intrinsic-
Membrane defects-Hereditary spherocytosis (HS)Enzyme-G 6 PD deficiencyHemoglobinopathies
– Extrinsic- AIHA (Auto-immune hemolytic anemia), DIC, IV hemolysis
Loss– Blood loss
QuestionA previously well African-American child visited Africa and was given malarial prophylaxis. He experienced pallor, fatigue, and dark urine. His hemoglobin level decreased from 14.8 to 9 g/dL.
SMEAR
An African-American child visited Africa and was given malarial prophylaxis. He experienced pallor, fatigue, and dark urine. His hemoglobin level decreased from 14.8 to 9 g/dL. The most likely
diagnosis is
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1. Hereditary spherocytosis
2. Sickle cell disease
3. Hepatitis4. G6PD deficiency
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Hemolytic anemia
History; Recent infection, drug exposure, illness, dark urine, anorexia, fatigue, pallorFamily h/o gallstones, splenectomyPhysical Examination: Pallor, tachycardia, tachypnea, splenomegaly.Peripheral smear: Blisters, spherocytes
Children with congenital spherocytosis have all of the listed conditions except:
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1. positive Direct Coombs 2. splenomegaly,
gallbladder stones 3. abnormalities in spectrin
and /or ankyrin4. increased MCHC5. abnormal osmotic
fragility test.
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Spherocytes
SpherocytesNucleated rbcCoombs-AIHAOsmotic fragility-HS
HS- with severe anemia
A 6 year old girl who has hereditary spherocytosis presents with a 1 week history of fever. Physical examination and history reveal abdominal pain, vomiting, fatigue and pallor. Her hemoglobin is typically about 10 g/dL with a reticulocyte count of 9%, but now, her hemoglobin is 4 g/dL and the reticulocyte count is 1%. Her bilirubin is 1 mg/dL. Of the following, the MOST likely cause for this girl’s present illness is infection with
– Coxsackie virus– Parvovirus B19– Epstein-Barr virus– Hepatitis A virus– Influenza A virus
HS- with severe anemia
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1. Coxsackie virus2. Parvovirus B193. Epstein-Barr
virus4. Hepatitis A virus5. Influenza A virus
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Newborn ScreeningYou get a call from a frantic parent because she received a letter from the State regarding her baby’s test results on NBS.FS- SS disease, S-B0 Thal, Sickle cell w/ HPFH.FSA- Sickle B+ thal, Sickle cell traitFSC- SC diseaseFAS- Sickle cell traitFAC- Hb C traitFAE- Hb E traitFE - Hb EE disease, E-Thal
Sickle cellHemolysis- life span 20-50 days. Abnormal cell shape, abnormal adherence to endothelium, decreased oxygenation, Increased polymerization.Symptoms start by 2-4 months of age.Hb electrophoresis, S >75 %.Start Penicillin daily and give until age 5. Prevention of pneumococcal infections.PPV (Pnu-23) age 2, 5Meningococcal vaccineFolic acid daily
The mother of a 10 month old baby with SS disease asks you about prognostic indicators. All of the following indicate likelihood of more
severe disease except:
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1. High WBC2. Associated alpha
thalassemia trait3. Low hemoglobin4. Repeated
episodes of dactylitis
Sickle cell crisesVaso-occlusive crisis-dactylitis, long bones, back, chest. Trt. Pain meds, hydration.Aplastic crisis: low Hb, low retic, Secondary to Parvovirus infection.Splenic sequestration crisis: spleen palpationHyperhemolytic crisis
Sickle cell Acute Chest Syndrome
New infiltrate on X-ray, fever, chest pain, back pain, hypoxia.Due to infarction, infection, BM fat embolismTreat: Antibiotics to cover pneumococcus, Mycoplasma, Chlamydia, Bronchodilator, Oxygen, Incentive spirometry, transfusion, Steroids (controversial).Avoid overhydration
Pulmonary Hypertension
Prevalence of pulmonary HT in SCD from 20-40 %.The presence of hemolysis, chronic anemia, and the need for frequent transfusions were directly associated with development of PHT.On follow-up, PHT was significantly associated with an increased risk of death. -Am J Hematol July 2004
-N Engl J Med Feb 2004.
TCD- Transcranial Doppler
A routine TCD on a 4 year old patient with SS disease shows a Cerebral blood flow (CBF) of 210 cm/second.What is the next step?STOP studies- STOP I and II
According to the STOP protocols, all children with abnormal TCD require enrollment in hypertransfusion
protocol till (choose one)
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1. Repeat TCD is normal
2. Continue indefinitely
3. the child reaches 18 years
4. MRA/MRI are reported normal
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Sickle cell and StrokeAffects 10 % of patientsInfarctive stroke (younger patients) and Hemorrhagic stroke (older)STOP I study established the role of yearly TCD (transcranial doppler) to measure cerebral blood flow velocity as a tool for determining stroke risk.Transfusion therapy as current therapy for high risk patients (CBF> 200cm/sec)Reversal of CBF velocity is not sufficient to stop transfusion therapy. (STOP II)
Sickle cell and TransfusionsTransfusion indications:– Acute anemia (Aplastic, Hyperhemolytic, Sequestration)– Hypoxia (ACS, chronic lung disease, Pulmonary hypertension)– Stroke and stroke prevention– Intractable pain, pre-operative preparation
Types of transfusions– Intermittent– Chronic simple– Exchange (Partial, Total, Erythrocytapheresis)– Hypertransfusion (transfusions in an effort to prevent patient
from producing their own red cells)
Which of the complications of sickle cell disease is more common in SC patients compared to SS disease
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1. Sickle retinopathy 2. Ischemic stroke3. Acute Chest
syndrome4. Pulmonary
Hypertension5. Leg ulcers
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Iron overloadOne unit -200mg IronNo physiologic way of removal 10-20 transfusionsDesferioxamine available. Can be given IV or subq infusion or subq shots.Compliance an issue.December 2005- Oral chelator available (Deferasirox)- FDA approved.
Sickle cell and Hydoxyurea
FDA approved for adultsStudies in children demonstrated efficacy and safety.Increases hemoglobin F levelIncreases hemoglobinDecreases WBC – ancillary effectHydroxyurea is recommended by the hematologist for patients who have recurrent vaso-occlusive crises, acute chest syndrome.
Other important points
Median life expectancy:– Males 42 years, females 48 years
Improvement related to Penicillin, immunizations, education.Bone marrow transplant (BMT) is a cureCord blood storage
A healthy 5 year old boy has a 2 day hx of fever, P/E normal, No hepatosplenomegaly, LN, no focus of infection. CBC WBC 3, Neutrophils 25 %, Hb 12,
Platelet 200X109/L, ANC 750. Most appropriate step is t
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1. Amoxicillin for 10 days
2. G- CSF for 10 days.3. BM aspirate4. Refer to a
hematologist5. Repeat CBC in 1-2
weeks6
NeutropeniaSevere neutropenia ANC < 500/mm3 Viral infection(hepatitis, Influenza, Measles, Rubella, RSV, EBV)- No Rx.Cyclic neutropenia– Sporadic Autosomal dominant disorder– 21 day intervals, nadir < 200/uL– G CSF treatment
Severe Congenital Neutropenia (Kostmann)– AR, ANC< 200, BM arrest, high dose G CSF, risk of
malignancy (MDS/AML) and sepsis. BMT cure.
NeutropeniaAuto-Immune neutropenia– Self limited, G CSF only if necessary– Mild infections
Schwachman-Diamond Syndrome– AR, Exocrine pancreatic failure, short stature, recurrent
infections, metaphyseal dysostoses.– G-CSF, Risk of myelodysplasia and AML, BMT curative
Chronic benign Neutropenia– ??AI, < 3 years of age, ANC < 200,skin and mucous membrane
infections, Normal marrow, AntibodiesEthnic neutropenia- (Benign familial)-AADrug Induced- Procainamide, Anti-thyroid, Sulfasalazine.
CaseA 2-year-old boy has had several 10-day-long episodes of fever, mouth ulcerations, stomatitis, and pharyngitis. These episodes have occurred at about monthly intervals. Absolute neutrophil counts have been 50/mm³on day 1 of each illness, 500/mm³ on day 10, and 1,500/mm³ on day 14.
Among the following, the MOST likely cause for the findings in this patient is
A. chronic benign neutropeniaB. cyclic neutropeniaC. Schwachman-Diamond syndromeD. severe congenital neutropeniaE.. transient viral bone marrow suppression
All of the following are true in CGD (Chronic granulomatous disease) except
Neurophils cannot destroy catalase positive organismsUnable to secrete Hydrogen peroxidePneumonia, Underweight, recurrent infectionsNitroblue Tetrazolium test is for diagnosisHave abnormal chemotaxis
Approach to a bleeding patient
History:– h/o trauma, H/o similar episodes– h/o bruising, h/o surgery in the past– h/o circumcision, bleeding from the umbilical
stump ,delayed wound healing– Time of onset (acute/chronic), any challenges
eg. trauma, surgery or menstruation– Overall health ( well / sick); Evidence of shock.– bleeding disorders in the family (maternal
uncles and aunts, grandparents)
Abnormal Bleeding
Epistaxis unrelieved by 15 minutes of pressure, both nostrils, requiring an ER visit, documented drop of hemoglobin. Menstrual periods( amount, pads, duration) Bleeding after procedures (circumcision, dental extractions, T and A-delayed bleed)Ecchymoses/bruising inconsistent with the degree of trauma
Bleeding patient
Physical Examination:Type of bleeding: Superficial or deep– Bruises, Petechiae– Epistaxis, Gum bleeding, Excessive menstrual
bleeding– Site of bleeding– Bleeding into the joints and soft tissues– Look for evidence of shock– Medication history (Aspirin, NSAIDS)
Coagulation cascade
Lab studies(What do they measure?)
CBC and Peripheral smearPT, INR and PTT– PT - Factor VII, common pathway– PTT- Factor VIII, IX, XI, XII, common pathway
Mixing studies (Inhibitors and deficiency)Specific coagulation factor assaysFibrinogen
Circulating anticoagulant
Mixing studyIf PT or PTT is prolonged, ask for a mixing study.Mix patient plasma with equal amount of normal plasma, the test will normalize if the abnormal result is because of a deficiency in factor. If there is an anticoagulant, it will not normalize or even if it does, it will become abnormal again after incubation.
Factor XIII and VII deficiencyFactor XIII
Rare Autosomal RecessiveIf all tests are normal:– PT, PTT, Platelet count and function, VW tests all normal.– Think of doing Factor XIII assay for deficiency
Bleeding after umbilical stump separationAbnormal clot solubility in 5M Urea
Factor VIIIntracranial hemorrhageRare, homozygous stateProlonged PT, n PTTTreatment with Recombinant F VII
A healthy 2-day-old boy born at term undergoes circumcision. Bleeding noted at the site 10 hours after the procedure and
increased steadily over the past 4 hours. Findings on exam are unremarkable except for bleeding along 2 to 3 mm of the surgical
site; no petechiae or purpura.
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1. Disseminated intravascular coagulation
2. Factor VIII deficiency hemophilia
3. Immune thrombocytopenic purpura
4. Neonatal alloimmune thrombocytopenia
5. Von Willebrand disease
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Bleeding disorders
Tests for bleedingHemophilia AHemophilia BHemophilia CVW Disease
Hemophilia
Factor VIII deficiency (Hemophilia A)-85%– X-linked recessive, Carriers asymptomatic– Severe<1%, Moderate 1-5, Mild 6-30 %– Treat Recombinant Factor VIII 1unit/kg raises factor
level by 2 %. Half life 12 hrs. DDAVP for mild cases.– Joint bleeds need100%, muscle bleeds 50 %.– 30 % develop inhibitors after infusions with
concentrate (Approx 50 infusions)Factor IX deficiency (Hemophilia B)– X-linked recessive, less common
A patient with Hemophilia A has asked you about the possibility of his children being affected by the
disease. The partner is normal.
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1. There is a 50 % chance that his sons will have the disease.
2. There is a 50 % chance that his daughters will be carriers
3. There is a 100 % chance that his sons will have the disease
4. There is a 100 % chance that his daughters will be carriers
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Case
13 year old girl just started her periods and has been bleeding for the past 16 days. She has used 14 pads a day and is tired. Her vital signs are stable, Hb 9.5, PT, PTT normal. The mother had heavy periods and her 6 year old brother has nose bleeds for the past 2 years.Likely to have:
Von Willebrand’s Disease1-2 % of population
Type I - 80 % of cases; Quantitative defect, Autosomal dominant (AD)Type 2 - 15-20 %, Qualitative defect– 2A, 2b (thrombocytopenia), 2M, – 2N (AR)
Type 3 - Severe (similar to hemophilia A)Autosomal recessive (AR)DDAVP- Releases VWF from endothelial cells and stabilizes Factor VIII– SE: Water retention, Tachyphylaxis, hyponatremia. – For mild Hemophilia, Type I VWD, 2– Contra-indicated in Type 2B
Plasma derived VWF containing concentrates
Thrombophilia- CaseA 14 year old male presents with chest pain and difficulty breathing. He notes that his right calf has been swollen for the last 3 days and he has difficulty placing his foot on the ground. P/E Pain on dorsiflexion, Air entry reduced. CXR and EKG are normal. VQ scan shows a filling defect and a diagnosis of DVT and pulmonary embolism is made.What are the important questions on history?– History of DVT in family members– H/o recurrent late miscarriages in mother and her sisters.– H/o trauma and precipitating factors
The most common cause of familial predisposition to thrombosis is
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1. Hemophilia antibodies
2. Protein C deficiency3. Protein S deficiency4. Factor V Leiden
mutation5. Antithrombin III
deficiency
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Causes
Factor V Leiden (Activated Protein C resistance)Prothrombin G 20210A gene mutation Protein C deficiency and activityProtein S deficiency and activity.Anti thrombin III deficiency and activity.HyperhomocystenemiaAntiphospholipid syndromeRare disorders-Dysfibrinogenemia
Hypercoagulable statesFactor V Leiden- 40-50 % cases– Abnormal factor V cannot be cleaved and inactivated
by Protein C & there is thrombosis.– Common in Caucasians (5.3 %)– Non-O blood group more prone to thrombosis– Homozygotes 1%
Protein C- Vit K dependent, produced in liver– Activated PC inactivates coagulation factors Va and
VIIIa, The inhibitory effect is enhanced by Protein S.– Venous thromboembolism, Neonatal purpura
fulminans, Warfarin-induced skin necrosis.
Hypercoagulable statesG20210A Prothrombin mutation– Increase in the prothrombin, a precursor of thrombin– Vitamin K-dependent protein which is synthesized in
the liver– Heterozygous carriers have an increased risk of deep
vein and cerebral vein thrombosis. Antithrombin (AT, formerly called AT III)– vitamin K-independent glycoprotein that is a major
inhibitor of thrombin and factors Xa and IXa. – In the presence of heparin, thrombin or factor Xa is
rapidly inactivated by AT; this is referred to as the heparin cofactor activity of AT.
Transfusion
A 4-year-old boy develops massive bleeding following a tonsillectomy. A transfusion is indicated, but his parents are extremely concerned about the risk of a transfusion-mediated infection. They want to know what tests are performed on donated units of blood before they consent to the procedure.Of the following, your discussion is MOST likely to include the statement that
your discussion is MOST likely to include the statement that
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1. all units are tested only for hepatitis B and C
2. all units are tested only for human immuno-deficiency virus (HIV)
3. all units are tested for HIV, hepatitis B, and hepatitis C
4. all units are tested for HIV, hepatitis B, hepatitis C, sickle cell trait, cytomegalovirus, and Epstein-Barr virus
5. only units obtained from donors who have one or more risk factors are screened for HIV, all units are tested only for hepatitis B and C
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Transfusion- Notes
CMV negative- give leukocyte reduced.Irradiated products- To prevent GVHDWashed cells- To reduce febrile reactionsPhenotype matched– To prevent allo-immunization
Sickle negative- In sickle cell patients, neonates
CANCER IN CHILDREN
Distribution-All agesChildhood Cancer Distribution Leukemia
Lymphoma
Brain Tumor
Soft tissue sarcoma
Germ call
Bone
Neuroblastoma
Renal
Retino
Hepato
Carcinoma
Other
Cancer in Children
Leukemias, Brain tumors, Lymphomas2nd leading cause of death 1-14yrs12,400 cases per year
Proto-Oncogenes imp for function-Activated
-Amplification --n-myc-Point mutation-NRA’s-Translocation- Ph chromosome t (9:22);
BCR-ABL
A 6-year-old girl has had diffuse aching in her arms, legs, and back for more than 2 weeks. Results of laboratory tests include hemoglobin, 9.4 g/dL; white blood cell count, 5,600/mm³ with no abnormal cells noted
on smear; and platelet count, 106,000/mm³. Radiographs of long bones reveal osteolytic lesions and radiolucent metaphyseal growth arrest
lines.
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1. acute lymphoblastic leukemia
2. Aplastic anemia3. Gaucher disease4. lead poisoning5. Multifocal
osteomyelitis
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ALL (Acute Lymphoblastic leukemia)Can present with generalized bone painBruising, nose bleedsUnusual fevers, infectionLymphadenopathy, hepatosplenomegaly
ALL (Acute Lymphoblastic leukemia)Abnormal to see blasts in the peripheral smearDiagnosis: >25 % blasts in the BM.Normal marrow has < 5 % blastsSingle most common childhood cancer (29% of all childhood cancers); 2500-3500 cases per yearPeak age 2-5 yearsMore likely in Trisomy 21, Ataxia-Telangiectasia, Bloom syndrome, Fanconi anemia.
ALL TreatmentInduction: 4-6 weeks, 95 % remission; Vincristine, Corticosteroids, L-Asparaginase and AnthracyclineConsolidation /delayed Intensification: 6-12 months; rotating drugs.Maintenance : Daily oral 6-MP, weekly MTX, Monthly pulses of Vincristine and Steroid.CNS prophylaxis: Intrathecal chemoCNS Therapy: RT + Intensive systemic chemoTesticular disease: RT
ALL- PrognosisPrognosis: WBC, Age, Cytogenetics – good if hyperdiploidy, trisomy 4,10,t (12,21)– Bad if Philadelphia chr t (9,22),t(4,11), t(8,14)
Immunophenotype: Pre-B, B, TEarly response, Minimal residual disease (MRD)Standard risk: 85 % survivalHigh risk: 65 % survivalVery low risk: 90% survivalInfants: 50 % survivalEarly relapse is a poor sign
Down Syndrome and Leukemia10-20 fold increaseALL : AML= 4 :1< 2 years: M7 AMLDS: 400 fold Increase in M7 AMLSuperior response to Rx of AMLTransient Myeloproliferative disorder in newborn which resolves within 3 months. – No clonal cytogenetic abnormality.
Rx : Exchange or low dose cytoreduction. Higher chance of M 7 AML. (30% in some reports)
Acute Myeloid Leukemia (AML)20 % of all leukemiasIncreased incidence in < 1 year of ageHigher incidence:– Downs, Fanconi, Bloom, DBA, Kostmann,
Neurofibromatosis I, Schwachman-DiamondSx: Fever, bleeding, pallor, anorexia, fatigue, Bone/Jt pain, LN, GI Sx.Chloromas (green) – solid collection in bone/soft tissuesTypes: M0-M7, commonest M2M7- Downs syndrome
Acute Myeloid Leukemia (AML)Treatment: – Remission Induction, Consolidation, Maint– BMT (matched sib donor) after remission.– ATRA (form of Vit A-transretinoic acid) in APML
Results:– HLA matched donor: 65 % EFS– No donor 40-50 %
Prognostic features:– Favorable: t(8,21), inv(16); Early remission;
FAB M4 with eosinophilia– Unfavorable: Monosomy 7; WBC> 100,000;
Secondary AML; Myelodysplasia with AML
All statements about Hodgkin’s disease are true except
0%0%0%0%
1 2 3 4
1. Has a better prognosis than Non Hodgkins
2. Can progress to acute leukemia
3. Fever, night sweats, wt loss are used for staging
4. Has a bimodal age distribution
6
Hodgkin’s LymphomaBimodal age distribution: first peak 20-30, again after age 50. Rare < 5 years.5 % of all malignancies; 40 % of lymphomas, Sx: Painless adenopathy, 1/3 have “B” symptoms( fever, night sweats, wt loss)Pathology: Reed-Sternberg cell (large cell with multilobed nuclei); B-cell, 4 subtypes.Rx: based on stage; Staging depends upon one side or both sides of the diaphragm. Stage !-2, EFS 85-90 %, Stage 3-4; 75 % EFS.Second malignancy in patients who have recd combination chemo and RT-- Leukemia, NHL, Breast cancer.
Non Hodgkins LymphomaMost common lymphoma in childhood10-15 % of all cancers (after leukemia, Brain tumor)50 % of all cancers in Africa (Burkitt’s)More in males, CaucasiansCommon in immunodeficiencies (SCID, Wiskott-Aldrich syndrome, HIV, following stem cell transplant.Types: – small, non-cleaved 40 % (B cell)– Lymphoblastic lymphoma 30 % (T cells)– Large cell 20 % (B, T, indeterminate)
Sites: Abdomen, mediastinum, head and neckMajority are high gradeChromosomal translocations involve c-myc oncogene (chr 8)
Burkitt’s LymphomaEndemic Burkitt’s – African type, head and neck, jaw– 95 % chance of EBV
Sporadic Burkitt’s – Abdomen– 15-20 % chance of EBV
Treatment- Early diagnosis, surgery, chemotherapy, Tumor lysis, Treatment based on stage and histology.Immunotherapy: Anti-CD 20 monoclonal antibody; (Rituximab)Prognosis: Stage Overall 70 % cure rate, early 85 %.
Case
5 yr old boy with progressive vomiting, headache, unsteady gait and diplopia for 4 weeks. MRI shows a contrast enhancing tumor in the 4th ventricle with obstructive hydrocephalus.
Medulloblastoma
- most common CNS tumor– Trt: Resection, Craniospinal RT, Chemo for
incompletely resected tumor and infants to permit smaller RT dose and recurrence.
– Prognosis: Age, large size, degree of resection, dissemination, histology.
Brain Tumors20% of all malignancies in childrenAge 3-7 yearsMost often infratentorial– cerebellar and hemispheric astrocytoma, medulloblastoma,
brain stem gliomas, Craniopharyngiomas.Sx: Persistent vomiting, headache, gait imbalance, diplopia, ataxia, vision loss, school deterioration, growth decelerationAssociations with Inherited Genetic disorders:– Neurofibromatosis, Tuberous sclerosis, Von-Hippel-Lindau
disease, Li-Fraumeni (glioma), Turcot syndrome
Wilms TumorAn 18-month-old girl is being evaluated because her mother thinks her abdomen seems “full.” Physical examination reveals an abdominal mass. Ultrasonography identifies a solid renal mass. At surgery, a stage I Wilms tumor is found.
Wilms Tumor
Histology: favorable(FH) vs unfavorable (UH)Staging: I-local, II-excised, III-residual, IV-metastases, V -bilateralTreatment: Nephrectomy, Chemo-all, St I-II-2 drugs-18 weeks, St III-IV- 3 drugs+ RTPrognosis: – FH: > 90% at 2 years– UH: < 60% at 2 years
Congenital anomalies associated with Wilms’ tumor include all of the following
except
1 2 3 4 5
0% 0% 0%0%0%
1. Polydactyly2. Aniridia3. Hemihypertrophy4. Cryptorchidism5. Denys-Drash
syndrome
6
Wilms Tumor
Associations: WAGR (Wilms, Aniridia, GU anomalies, MR)– Beckwith-Weidemann syndrome- organomegaly,
hemihypertrophy, omphalocoele)(chr 11p15.5 gene deletion)3-5 % risk of WT (general population 8.5/mill)
– Denys-Drash: Pseudohermaphroditism, nephropathy– Perlman syndrome: Macrocephaly, macrosomia
Do Ultrasound, Urinalysis q 3-4 monthsChest Xray needs to be followed
A 9 year old previously healthy girl manifests progressive painless proptosis and decreased visual acuity of the left eye during a 2 month
period. The most likely diagnosis is
1 2 3 4 5
0% 0% 0%0%0%
1. Pseudotumor of the orbit
2. Trichinosis3. Retinoblastoma4. Rhabdomyosarco
ma5. Orbital cellulitis
6
Rhabdomyosarcoma7 % of all childhood cancersPainless non tender mass, 60% under age 6Sites: head & neck, GU, Extremities, mets lungs.Majority sporadic, associations: B-W, Li Fraumeni, NF 1Types:– Embryonal 70%, better prognosis– Alveolar 30 %, trunk, worse prognosis
Treatment: Surgery, Chemo, local control RTResults: – 85 % good risk– 30 % metastatic disease
MassThe mother of a 22-month-old boy reports that he has been fussy and tired. Findings on physical examination confirm the presence of a nontender rt upper quadrant mass. Bilateral periorbital ecchymoses also are noted.Of the following, the MOST likely cause for these findings isA. multicystic kidney diseaseB. neuroblastomaC. non-Hodgkin lymphomaD. HepatoblastomaE. Wilms tumor
All statements are true about Neuroblastoma except:
1 2 3 4 5
0% 0% 0%0%0%
1. Most common extra-cranial solid tumor
2. Prognosis better with N-myc oncogene amplification and tumor diploidy (DNA index 1)
3. Most common cancer in the first year of life
4. Frequent in <4 years, 97 % cases by 10 years
5. Most commonly diagnosed as Stage III or IV
6
NeuroblastomaLow risk:– Surgery alone; >95 % 5 year survival
Intermediate risk:– Surgery and Chemo; 80-90 % 5 year survival
High risk:– Induction chemo, surgery, Chemo with autologous
transplant, RT, Biologic therapy– 30 % 5 year survival
Stage IVs- Localized primary tumor with spread to skin, liver and/or bone marrow- Minimal therapy.
A 16 year old male comes in because he fell in the supermarket.P/E shows a small painless mass on the medial aspect of the knee.X ray shows a fracture and a lytic sunburst pattern. (periosteal elevation)What is your diagnosis?What would you do next?
Osteogenic Sarcoma- X ray and MRI
Osteogenic SarcomaMRI, Bone scan, Biopsy, CT Chest. Peak incidence- 2nd decadePredisposition: Hereditary retinoblastomas, Li-Fraumeni, Pagets, RT, Alkylating agents60 % near the knee (Metaphyses of long bones)History of fall, pain common symptom, mass, no systemic symptoms.Treatment: Open biopsy, Sperm banking, Neo-adjuvant Chemotherapy, limb preserving surgery.
A 16 year old Caucasian female comes with complaints of chest pain and difficulty breathing for the past one week. She has had fever, wt loss over the last 2 months. She has reduced air entry and CXR shows a moth eaten appearance of one of the ribs and a pleural effusion.Biopsy is done and is consistent with
Ewing’s SarcomaSeen in Axial bones, flat bones and long bones. 20 % in soft tissue.Caucasians, Onion skin appearance, Diaphysis affected.MRI, CT Chest, Bone scan, Biopsy, BM aspirate and biopsy( Anemia).Unique marker: t(11,22) most casesPNET: Ewing like tumor with neural differentiationTreatment:– Surgery, RT, Neoadjuvant Chemo,
Ewing’s Sarcoma
RetinoblastomaPresentation:– Leukocoria (cats eye reflex), dilated pupil, esotropia, strabismus
Unilateral 75 % (could be hereditary/non)– 60 % unilateral and non hereditary– 15 % unilateral and hereditary (RB1 mutation)
Bilateral 25 %– 25 % are bilateral and hereditary, have RB1 mutation– Earlier age, 11mos, Can develop in each eye separately– Higher incidence of sarcoma, melanoma, brain tumors.
10 % of retinoblastoma cases have family history.But child of parent with the RB1 gene (Chromosome 13q) has a 45 % chance of developing the tumor.
Retinobalstoma
A child with ALL was started on Chemotherapy. She had a WBC 82,000, Hb 9gm, plt ct 45,000. She develops tumor lysis syndrome: Which one depicts Tumor lysis
1 2 3 4 5
0% 0% 0%0%0%
1. K high, P high, LDH normal, Na high
2. K high, P normal, LDH high, Na nl
3. K normal, P high, LDH high, Na high
4. K normal, P normal, LDH high,
Na normal5. K high, P high,
LDH high, Na normal.
6
Tumor lysis syndrome
Rapid destruction of cancer cells.Release of intracellular ions, also Uric acid, can cause tubular obstruction and damage.Treatment: Allopurinol or Rasburicase early, hydration, alkalinization, diuretic therapy.
Spinal cord compressionLocal tumor extension or metastasisLymphomas, neuroblastoma, soft tissue sarcomasPresentation: back pain worse with movement, neck flexion, straight leg raising, valsalva– Weakness; partial/complete paralysis, Incontinence
Diagnosis: Clinical / Spinal MRITherapy: Urgent treatment to relieve pressure and prevent permanent neurologic damage. – Neurology/Neurosurgery consult– High dose dexamethasone– Emergency radiation therapy– Laminectomy
Superior Vena Cava SyndromeMass lesion obstructs flow through the SVCSx due to engorgement of collateral veins of thorax, neck and head– Dyspnea, edema of face, neck, upper extremities– Periorbital edema, conj edema (itchy eyes)– Dysphagia,resp distress, vocal cord paralysis
Tracheal compression: resp distress, wheezingNHL, Tcell ALL, Lymphoma, TeratomaSecondary cause: occluded central venous catheterTry to get a diagnosis before therapy
Chemotherapy-Side effects
Anthracyclines: CardiomyopathyVincristine: foot drop, neurologicalCisplatinum: kidney, deafnessMethotrexate, 6MP: Liver toxicityBleomycin: Pulmonary fibrosisAsparaginase: PancreatitisCyclophosphamaide: Hemorrhagic cystitis– (MESNA, Uroprotector)
Fever, Neutropenia
Single most important risk factor: ANCOrganisms: Gram negative, Staph epi in catheter patientsMedication: Broad spectrum 3rd generation antibioticsAnti-fungal after 4 daysExamine patient thoroughly
16-year-old girl, completed therapy at age 8 for Hodgkins disease with Involved field RT and chemo. She now develops petechiae, purpura, lymphadenopathy and
hepatosplenomegaly.Lab include: plt 12,000,Hb 8.0 gm/dL; and WBC 13,000/mm³
1 2 3 4 5
0% 0% 0%0%0%
1. acute myeloid leukemia as a second malignancy
2. disseminated varicella3. drug-induced ITP4. late-onset aplastic
anemia due to chemotherapy
5. viral-induced ITP
6
You are evaluating a 9 year old child for short stature. She was treated at 3 yrs of age for ALL, received cranial RT. Her height is < 5th percentile and she is Tanner stage I.
Most likely to have an abnormal test of
1 2 3 4 5
0% 0% 0%0%0%
1. Growth hormone 2. Estradiol3. Follicle stimulating
hormone4. Gonadotropin
releasing hormone5. Thyroid stimulating
hormone
6
Late effects of cancer therapy
RT: Hypothalamic pituitary axis is impaired;
central hypothyroid and Adrenal insuff. RT doses higher in brain tumor GH is dose sensitive to the effects of
RT Age related: < 5 years susceptible Panhypopituitarism with higher doses ovarian failure with RT
A 16 year old boy is receiving chemo for rhabdomyosarcoma with a year of cycles of
Vincristine, Actinimycin-D and Cyclophosphamide. Most likely endocrinologic late effect of this therapy
1 2 3 4 5
0% 0% 0%0%0%
1. Growth hormone deficiency
2. Hypothyroidism3. Impotence4. Infertility5. Osteoporosis
6
Chemotherapy effects
Chemotherapy with alkylating agents Females:
less effects than males normal puberty early menopause
Males:irreversible gonadal toxicitysterility with azospermiaPuberty usually not affected (leydig
cells)
The most common reason for the failure of hematopoietic stem cell transplantation is
1 2 3 4 5
0% 0% 0%0%0%
1. Veno-occlusive disease of the liver
2. Disease recurrence
3. Infection4. Graft vs. host
disease5. Graft rejection
6
GVHD ( Graft vs Host disease): All are true except
1 2 3 4 5
0% 0% 0%0%0%
1. It is the reaction of the donor lymphocytes against the host.
2. Acute GVHD starts within the first 100 days and chronic is after 100 days.
3. Affects the skin, liver and GI tract
4. Irradiation of blood products does not help
5. Complete HLA matching prevents GVHD
6
Germ cell tumors
2-3 % of Pediatric malignanciesTeratomas arise from endoderm, ectoderm and mesodermMarkers:– Endodermal sinus tumors –Alpha feto protein– Embryonal Ca, Choriocarcinoma- HCG
Mature teratomas- excision onlyImmature Teratomas: Surgery + Chemo
Other topics- do read
HistiocytosisStorage disorders
GOOD LUCK