AML

SCID (severe combined immunodeficiency)

- Defect in early *stem cell differentiation* - 7 different gene defects: *adenosine deaminase deficiency* - *No B or T! only NK cells left!* 1. Severe recurrent infections - chronic mucocutcandidiasis - fatal / recurrent *RSV, VZV, HSV, measles, flu, parainfluenza* - *PCP pneumonia* 2. *Chronic diarrhea* 3. *Failure to thrive* - *No thymic shadow on newborn CXR* (also seen in diGeorge)

Fanconi Anemia (FA)

(AR, AD, XL) disorder characterized by chromosomal instability. Patients have a complex assortment of congenital anomalies in addition to a progressive bone marrow hypoplasia.

Common variable immunodeficiency

-Defect in B-cell differentiation. Many causes. -Can be acquired in 20s-30s; increased risk of autoimmune disease, bronchiectasis, lymphoma, sinopulmonary infections. -Decreased plasma cells, decreased immunoglobulins.

DICER1

14q32.13 Plueropulmonary blastoma (PPB) Cystic nephroma Sertoli-Leydig ovarian stromal tumors Kidney tumors: cystic nephroma, anaplastic sarcoma of kidney, Wilms' tumor Differentiated thyroid tumor Rhabdomyosarcoma Pineoblastoma

A 12-week-old female infant is being evaluated for neonatal anemia. She has a hemoglobin of 5.4 g/dL, mean corpuscular volume of 98 fL, reticulocyte count 0.9%, WBC count of 5,890/mcL, absolute neutrophil count of 1,020/mcL, and platelet count of 170,000/mcL. She was born at 35 weeks gestation after an uncomplicated pregnancy. There were no neonatal problems, and jaundice was not present. She has gained weight and grown well since birth along the 3rd percentile for age. No blood loss has been noted. She is the first child for both parents. The father was transfused multiple times for anemia as a small child. The mother has well-controlled hypertension. What is the most likely diagnosis of this patient? a. Diamond-Blackfan anemia (DBA) b. Dyskeratosis congenita (DC) c. Fanconi anemia (FA) d. Shwachman-Diamond syndrome (SDS) e. Transient erythroblastopenia of childhood (TEC)

A The presentation of a severe macrocytic anemia, particularly in association with mild neutropenia, in the first few months of life should raise concern for an inherited bone marrow failure syndrome (IBMFS). The differential diagnosis would be unrecognized feto-maternal (or neonate-placental) bleeding and undetected ABO, RH, or other blood group incompatibility causing hemolytic disease of the newborn. By this age, there should be some reticulocytosis to suggest these diagnoses. The anemia is too severe for the expected physiologic nadir in a late- preterm infant who has been well. Dyskeratosis congenita usually presents in adolescence or early adulthood, so it is unlikely. Fanconi anemia can present in the newborn period, but thrombocytopenia and neutropenia are more common than marked macrocytic anemia in the newborn. This patient has only mild neutropenia and no pancreatic malabsorption symptoms to suggest Shwachman-Diamond syndrome. Patients with both Diamond- Blackfan anemia (DBA) and transient erythroblastopenia of childhood (TEC) may also have thrombocytopenia and neutropenia, but these associated cytopenias are at least twice as common in DBA. Further, TEC does not usually present so early in life. However, in this patient the history of transfusion requiring anemia in the father suggests that perhaps he also has DBA and, like 20% to 25% of patients, experienced a remission by age 25. The lack of congenital anomalies does not decrease the likelihood of an IBMFS. The marked macrocytic anemia, reticulocytopenia, and suggestive family history make option A, DBA, the best answer.

You are consulting on a 10-year-old male with severe persistent neutropenia, a history of recurrent infections, and warts. The rest of the peripheral blood count is normal. His mother also has neutropenia. Bone marrow examination shows a hypercellular marrow and retained myeloid cells with vacuolated cytoplasm. There are no abnormalities in the red cells or platelet precursors. Cytogenetics are 46XY. You start granulocyte colony stimulating factor therapy and the neutrophil count increases. A mutation in which of the following genes is most likely to have caused this familial inherited bone marrow failure syndrome? a. CXCR4 b. ELANE c. GATA 2 d. Mitochondrial DNA e. SBDS

A This patient has isolated neutropenia, with associated infections, and warts. While all of the genes listed are associated with an inherited bone marrow failure syndrome (IBMFS) with neutropenia, the one associated with myeloid hyperplasia of the marrow is CXCR4, which is mutated in myelokathexis/WHIM syndrome. In WHIM syndrome (neutropenia with warts, hypogammaglobulinemia, infections, and myelokathexis), autosomal dominant mutations in CXCR4 cause a gain of function defect that results in a limitation of down regulation after stimulation. Granulocyte colony stimulating factor (G-CSF) ameliorates the neutropenia and apoptosis as well as the hypogammaglobulinemia that accentuates the infections seen in the disorder. While ELANE, which is mutated in many of the congenital neutropenia syndromes and SBDS in Shwachman-Diamond syndrome, cause neutropenia and will respond to G-CSF, they are not associated with warts or a hypercellular marrow unless malignant transformation has occurred. Mitochondrial DNA mutations are seen in Pearson syndrome in association with vacuolated marrow precursors and ringed sideroblasts (the later are absent here), usually in a patient with a history of metabolic disturbances, exocrine pancreatic dysfunction, and thrombocytopenia. The neutropenia of Pearson syndrome is not usually severe enough to require G-CSF when the patient is otherwise well. GATA 2 mutations are associated with MonoMAC syndrome (among others) whose hallmarks are monocytopenia, recurrent mycobacterial infection, and warts).

NF1

AD Tumor Suppressor (2 hit), Ch. 17 NeuroFibromatosis type 1 or Von Recklinghausen's Ras GTPase activating protein (neuro bromin) RMS, optic glioma, showanoma

Rac2GTPase def

AD symaler to LAD1 impaired oxidative burst

t(8;21)(q22;q22) is diagnostic for what condition?

AML-M2 most common cytogenetic abnormality in children with AML and confers a favorable prognosis. Distinctive pathologic features of myeloblasts include indented nuclei, basophilic cytoplasm, and easily identifiable Auer rods. Leukemogenesis is thought to occur as a result of altered transcriptional regulation of RUNX1 target genes and activation of new genes that prevent apoptosis or cell differentiation.

Hermansky-Pudlak syndrome

AR - fibrosis and honeycombing in lungs, oculocutaneous albinism, platelet dysfunction (storage pool), Cyclic neutropenia, partial albinism, HLH as well as Bowel Disease

Acute promyelocytic leukemia (M3) (treatment)

All-trans retinoic acid Problem with Retinoic Acid Receptor (prevents cellular differentiation) --> give all-trans retinoic and enable differentiation treatment of AML in terminal differentiation of promyelocytes.

IRAK4 deficiency

An immunodeficiency characterized by recurrent bacterial infections, caused by inactivating mutations in the IRAK4 gene that result in a block in TLR signaling.

Fusion neg RMS

Aneuploidy, Activation RAS pathway, LOH or LOI 11p15.5 ( p53, NCOA2 or VGLL2 rearrangements (Favorable infants /w spindle cell)

An 18-year-old patient presents with acute myeloid leukemia (AML). He had severe neutropenia first noted in infancy and had a history of recurrent bacterial infections and oral aphthous ulcers. The neutrophil counts rose to normal and the infections resolved after the initiation of G-CSF. Analysis of the leukemic clone revealed an acquired mutation in the cytoplasmic domain of the G-CSF receptor. Which gene mutation would probably be constitutionally present in this patient? a. c-Mpl b. ELA2 c. FANCA d. FLT3 e. RPS19

B The vignette describes a typical case of severe congenital neutropenia (SCN or CN). Of the choices given, only ELA2 mutations are associated with SCN or CN. Mutations in the granulocyte-colony stimulating factor (G-CSF) receptor frequently arise in patients with severe congenital neutropenia and result in constitutive activation of the G-CSF receptor. The clinical significance of these mutations is not clear because some mutant G-CSF clones progress to leukemia while others remain stable for many years. However, development of acute myeloid leukemia (AML) with an acquired mutation in the cytoplasmic domain of the G-CSF receptor is a commonly observed event in patients with SCN after prolonged therapy with G-CSF. RPS19 mutations are associated with Diamond-Blackfan anemia. C-Mpl mutations are associated with congenital amegakaryocytic thrombocytopenia. FANCA mutations are present in Fanconi anemia group A. FLT3 is the most commonly mutated gene in AML, but it would not usually be a constitutional mutation.

You are evaluating a 10-year-old girl for thrombocytopenia. Careful review of the blood counts reveals macrocytosis, as well. The child is less than 5th percentile for height and weight, has no skin lesions, no history of malabsorption, and no history of cancer in the family. Bone marrow biopsy is less than 5% cellular with no dysplasia. Which of the following tests is the most important to help you clarify the diagnosis and plan therapy? a. Erythrocyte adenosine deaminase activity (eADA) level b. Diepoxybutane (DEB)/mitomycin C (MMC) chromosomal breakage assay c. Mitochondrial DNA deletion analysis d. Pancreatic isoamylase level e. Paroxysmal nocturnal hemoglobinuria (PNH) clone analysis

B This patient has aplastic anemia, but you do not know if it is congenital or acquired. It is imperative that you screen for the presence of increased chromosomal breakage (suggesting a diagnosis of Fanconi anemia [FA] or other DNA repair syndrome), which would necessitate alternative therapy: reduced conditioning for a hematopoietic stem cell transplant or androgen instead of immunosuppressive therapy. The short stature may suggest a diagnosis of FA or indeed any inherited bone marrow failure syndrome (IBMFS), but increased chromosomal breakage in response to diepoxy butane (DEB) or mitomycin C (MMC) is required to support the diagnosis. If the screen were positive, chromosomal evaluation for a known mutation would be sought to confirm the diagnosis and allow precise evaluation of siblings and potential donors for the disorder. If the DEB/MMC testing were negative and you still strongly suspected FA, a skin biopsy could be obtained and the fibroblasts grown to confluence and then tested for FA mosaicism. The extent of the evaluation for IBMFS is guided by clinical suspicion. For example, a history of malabsorption would suggest screening for Schwachman-Diamond syndrome with pancreatic isoamylase (> 3 years old) or trypsinogen ( Elevated erythrocyte adenosine deaminase activity (eADA) levels are seen with Diamond-Blackfan anemia (DBA), which typically presents with macrocytic pure red cell aplasia. While some DBA patients may also have some degree of thrombocytopenia or neutropenia, it is rare at diagnosis. An increased proportion of cells missing glycosylphosphatidylinositol (GPI)-linked protein are seen with paroxysmal nocturnal hemoglobinuria (PNH). Screening for a PNH clone is recommended at presentation of aplastic anemia, but it is not critical to direct therapy. Mitochondrial DNA deletions are associated with Pearson syndrome, and vacuolated precursors should have been present in the marrow.

A 15-year-old girl returns for routine follow-up 8 years after immunosuppressive therapy (IST) with antithymocyte globulin (ATG) and cyclosporine for severe aplastic anemia. She had a good response to IST, with normalization of her peripheral blood counts. Annual paroxysmal nocturnal hemoglobinuria (PNH) clone testing has shown no loss of glycophosphatidylinositol (GPI)-linked proteins. She does not have any siblings. Her blood counts show pancytopenia with a hemoglobin of 8.5 g/dL, MCV of 108 fL, WBC of 1,200/μL with 10% neutrophils, and platelets of 15,000/μL. What is the most important next step in management? a. Analyze DNA breakage analysis with DEB/MMC b. Evaluate bone marrow cytogenetics c. Measure PNH clone size by flow cytometry d. Obtain HLA typing e. Perform telomere length testing

B. Relapse of aplastic anemia following immunosuppressive therapy (IST) with anti-human thymocyte globulin (ATG) and cyclosporine is common (occurring in up to 30% of patients in some series), but relapse occurring this late is unusual. Patients treated with IST are at increased risk for developing clonal cytogenetic abnormalities, including monosomy 7, as well as leukemic transformation. Thus, a bone marrow aspirate and biopsy with cytogenetics would be the next step to evaluate the etiology of her recurrent pancytopenia and guide treatment. If morphologic evidence of myelodysplastic syndrome, cytogenetic abnormalities, or leukemia are present, therapy would include hematopoietic stem cell transplantation (HSCT). If none of these are present, and there were still no options for HSCT or the family declines HSCT, then repeat treatment with ATG, cyclosporine, and possibly eltrombopag should be planned. Although reevaluation at relapse should include reassessment of the size of the population of glycosylphosphatidylinositol (GPI)-deficient cells (paroxysmal nocturnal hemoglobinuria [PNH] clone), this is not the most important test to be evaluated. Diepoxybutane (DEB) or mitomycin C (MMC) testing for DNA breakage should have been done with the first presentation, and a patient with Fanconi anemia or another breakage syndrome would have been unlikely to respond to immunosuppressive therapy and maintained normal counts for years. Patients who experience a relapse of their aplastic anemia soon after immunosuppression is withdrawn may be rescued with cyclosporine alone or with combined IST. HLA typing for an unrelated donor should have been done at initial presentation, even without a sibling to be prepared for a poor response to IST. Telomere length testing may be of interest, but again it may have been done with initial presentation and does not influence the care of a patient who had a long initial response to IST. At this time, the most important diagnostic evaluation is to reexamine the bone marrow with morphology and cytogenetics to rule out the acquisition of malignant or premalignant changes.

You are called to the nursery to see a newborn baby with cutaneous and mucosal bleeding. The platelet count is 20,000/mm3. The other blood counts are normal. Labor and delivery were uncomplicated, and maternal platelet counts are normal. The mother was not taking any medications that would affect the platelet count. There are no signs of infection. On exam, the baby's lower arms appear abnormal, but normal thumbs are present bilaterally. Which of the following is the most likely diagnosis? a. Acquired aplastic anemia b. Amegakaryocytic thrombocytopenia c. Diamond-Blackfan anemia d. Shwachman-Diamond syndrome e. Thrombocytopenia absent radii (TAR) syndrome

Both Fanconi anemia and TAR syndrome are autosomal recessive disorders that may present with radial ray (forearm) anomalies and low platelets in infancy. In TAR syndrome, the defect is intercalary, with missing radii and normal thumbs. In Fanconi anemia the defect is terminal; if the patient has an absent radius, the thumb on that side will also be abnormal or absent. Amegakaryocytic thrombocytopenia may present with thrombocytopenia early but not absent radii or thumb anomalies. Shwachman-Diamond syndrome may present with cytopenias early in life, but radial ray anomalies have not been commonly reported. Diamond-Blackfan anemia presents with red cell aplasia and present radii, although the thumbs may be digitalized (look like a finger). Acquired aplastic anemia is not typically associated with congenital anomalies.

C19) Adoptive Cellular Therapy for Solid Tumors: Prior Experience, Challenges, and Potential for the Future The family of a 9-year-old child with infiltrating diffuse intrinsic pontine glioma is interested in receiving cell therapy for their disease through a human clinical trial. Which of the following is NOT an example of adoptive cellular therapy? a. Tumor-infiltrating lymphocyte (TIL) therapy b. Chimeric antigen receptor (CAR) modified T-cells c. Immune checkpoint inhibitors d. Natural killer (NK) cell therapy

C . Lymphocyte (TIL therapy), CAR T-cells, and NK cells are all examples of cell therapies, exogenously engineered, to activate an immune response. Checkpoint inhibitors frequently involve the use of monoclonal antibodies directed against immunologic 'brakes' (eg, programmed cell death protein 1 (PD-1)) to rescue an endogenous cellular response.

A 12-year-old girl with severe aplastic anemia was treated with antithymocyte globulin (ATG) and cyclosporine. One week after completion of treatment with ATG, she developed a fever to 38.6 °C and an erythematous maculopapular serpiginous rash along the borders of her palms and soles. She also complained of pain in her knees, hips, and back. Blood cultures are negative. What is the most likely cause of her symptoms? a. Graft-versus-host disease (GVHD) b. Reaction to antibiotics c. Serum sickness d. Transfusion reaction e. Viral infection

C Serum sickness is caused by the formation and deposition of immune complexes and complement fixation in response to the foreign protein. Symptoms usually develop 5 to 11 days after the first dose of ATG. The pattern of distribution for this rash on the borders of palms and soles is classic. Other symptoms include fever, myalgias, arthralgias, and joint swelling. Gastrointestinal and neurologic symptoms, as well as transient renal dysfunction, also may occur. Infectious causes must be promptly evaluated and ruled out because the patient is very immunocompromised at this stage. Transfusion-associated GVHD may result from the transfusion of nonirradiated blood products into an immunocompromised host but would present as profound pancytopenia. Although viral infection or a reaction to antibiotics or blood products is possible, they do not present with fever and this type of rash.

Cartilage-hair hypoplasia

Characteristics misshaped limbs= short decreased ROM sparse light colored hair normal intelligence lymphopenia and neutropenia

You are evaluating a 17-year-old male with a 5-year history of mild but stable thrombocytopenia (platelet count 105-120,000/mL, MPV normal). Today his WBC is 6,000/mL with 38% neutrophils, hemoglobin 13.2 g/dL, MCV 110 fL, and platelet count 115,000/mm3. Bone marrow examination was hypocellular with no dysplasia and normal cytogenetics. Diepoxybutane (DEB)/mitomycin C (MMC) testing showed no increased breakage. B12 and folate levels are normal. His father has oral squamous cell carcinoma, and his paternal grandmother is on oxygen therapy; his mother is healthy. No one in the family smokes. The patient's physical examination today is remarkable only for a new white patch on the right side of his tongue. Which of the following tests will be most helpful in establishing a diagnosis? a. c-Mpl sequence analysis b. Fanconi anemia (FA) genetic testing c. Platelet antibody testing d. Telomere length analysis e. WAS gene testing

D Longstanding cytopenias with macrocytosis are frequent features of inherited bone marrow failure syndromes. In this patient, the new white patch on the tongue could represent oral leukoplakia, a premalignant finding associated with dyskeratosis congenita (DC) and Fanconi anemia (FA). In patients with both of these syndromes, suspicious oral lesions should be biopsied promptly. The family history in the vignette is consistent with an autosomal dominant pattern of inheritance, with a father who had oral squamous cell carcinoma and a paternal grandmother with lung disease that could be pulmonary fibrosis. This inheritance pattern is seen more commonly in DC than in FA, where inheritance of all genotypes is autosomal recessive except FANC-B, which is X-linked. The inheritance patterns of DC vary, depending on the mutated gene, and may be autosomal dominant, autosomal recessive, or X-linked. Telomeres will almost always be very short in multiple hematopoietic cell lineages in DC, and this is the recommended screening test for this disorder. A positive finding would be followed up by sequential genetic testing for mutations in the telomerase or shelterin complex. Although thrombocytopenia may be seen with c-Mpl mutations, which occur in congenital amegakaryocytic thrombocytopenia, the platelet counts are lower and the disease progresses more quickly than in this older teen. The MCV (mean platelet volume) is normal, arguing against WAS mutations, which is generally associated with very small platelets. Platelet antibody testing is not standardized, of unclear utility in chronic thrombocytopenia, and would be of most help with immune thrombocytopenia with large platelets. None of these other syndromes is associated with an increased risk of leukoplakia or squamous cell carcinomas. This patient had negative diepoxybutane (DEB)/mitomycin C (MMC) testing previously. If the test were convincing that there was no increase in breakage, then FA genetic testing is not generally advised.

A 6-year-old boy presents with a 1-week history of bruising all over his body, fatigue, and fever. His CBC shows pancytopenia. A bone marrow biopsy has 20% cellularity. Which of the following values would be most diagnostic of severe aplastic anemia? a. Absolute phagocyte count of 480/μl b. Hemoglobin of 7.9 g/dL c. Mean cell volume of 90 fL d. Platelet count of 10,000/μl e. Total leukocyte count of 900/μL

D Severe aplastic anemia is classically defined as a bone marrow cellularity of less than 25%, or 25% to 50% with less than 30% hematopoietic cells, and two of the following: ANC less than 500/μL, absolute reticulocyte count less than 40,000/μL, or platelet count less than 20,000/μL. Hemoglobin, total leukocyte, and absolute lymphocyte or phagocyte counts are not criteria for severe aplastic anemia. Similarly, increased mean cell volume (with a normal red cell distribution width) and percentage of fetal hemoglobin and little-i antigen, which are features commonly associated with aplastic anemia, also are not diagnostic criteria.

You examine a 10-year-old boy with severe aplastic anemia. He has no dysmorphic features and is at the 50th percentile for height and weight. Family history includes a sister with aplastic anemia unresponsive to anti- human thymocyte globulin (ATG) and cyclosporine who died early in the course of an unrelated donor hematopoietic stem cell transplant complicated by severe mucositis and transplant-related organ toxicities. There are no other siblings. A cousin died of acute myeloid leukemia at age 5 years. A peripheral blood sample test for Fanconi anemia is negative with no increased chromosomal breaks in response to diepoxybutane or mitomycin C. Which of the following is the most important next step in management? a. Administer ATG and cyclosporine. b. Search for a donor for matched unrelated transplant. c. Send a bone marrow aspirate for Fanconi anemia testing. d. Send a skin fibroblast culture for Fanconi anemia testing. e. Start oral therapy with oxymetholone.

D. A family history of a sibling with aplastic anemia and a cousin with pediatric acute myeloid leukemia raises the possibility of an inherited bone marrow failure syndrome (IBMFS) even in the absence of other clinical stigmata such as congenital anomalies. The significant transplant-related toxicity experienced by the sibling is suggestive of an IBMFS such as Fanconi anemia. A reduced-intensity transplant conditioning regimen would be indicated for a patient with Fanconi anemia. Peripheral blood tests for Fanconi anemia may be negative if the lymphocytes have reverted to wild type (somatic mosaicism). The gold standard to establish the diagnosis of Fanconi anemia or conclusively exclude it in this situation is to test skin fibroblasts. There is no advantage to testing the bone marrow aspirate for chromosomal breakage because somatic mosaicism also has been reported in the hematopoietic cells, and chromosomal breakage assays have not been standardized for marrow samples. Patients with Fanconi anemia typically fail to respond to anti-human thymocyte globulin and cyclosporine therapy for aplastic anemia. Oxymetholone is commonly used to support blood counts in Fanconi anemia patients but should not be considered until a diagnosis is confirmed and transplant options considered.

LAD-3: Found where in the body Along with immune defects ___________________ is also present (IIb/IIIa integrin receptor) Death due to __________ complications

Defective integrine activation , impaired NK function, Osteoporosis due to osteoclast defect bleeding due to platelet dysfunction

A 16-year-old girl with dyskeratosis congenita (DC) has had a rapid, progressive decline in her blood counts, which are currently a hemoglobin of 6.8 g/dL, ANC of 380/μL, and platelets of 22,000/μL. Her last annual surveillance bone marrow examination showed no evidence of myelodysplastic syndrome, and cytogenetics including fluorescent in situ hybridization were normal. She has had no invasive infections or bleeding. She is taking no medications. She has no full siblings. What is the best long-term treatment for this child at this time? a. Antithymocyte globulin (ATG) and cyclosporine b. Monitoring blood counts and observing clinical status c. Granulocyte colony-stimulating factor (GCSF) d. Oxymetholone e. Unrelated donor transplant with reduced-intensity conditioning

E Although the usual management for a patient with dyskeratosis congenita (DC) in childhood is quarterly monitoring of blood counts and consideration of bone marrow examination including cytogenetics periodically once the counts start to decline, this patient with DC has very low blood counts, at the level where transfusions likely soon will be required. Thus, continued observation is insufficient treatment. Antithymocyte globulin (ATG) and cyclosporine, the immunosuppressive therapy recommended in severe idiopathic aplastic anemia, has no role in the treatment of DC. While granulocyte-colony stimulating factor (G-CSF) and oxymethalone therapy alone or in combination may increase granulocyte numbers and perhaps all blood counts for several years, their use, particularly together, has been associated with splenic peliosis and splenic rupture in DC. This teenage patient is young enough, with low enough blood counts, that curative therapy with unrelated donor hematopoietic stem cell transplant should be pursued at this time. Patients with inherited bone marrow failure syndromes (IBMFS) that involve DNA repair defects, such as DC and Fanconi anemia, have increased sensitivity of other body tissues to alkylating agents and radiation, increasing the risk of transplant morbidity and mortality with standard transplant regimens. Conditioning regimens with lower doses of cyclophosphamide, lower dose or no radiation, substitution of fludarabine, and in some circumstances T-cell depletion have resulted in improved transplant outcomes for IMBFS patients. However, IBMFS patients also have a higher risk of malignancy in tissues outside of the marrow posttransplant. DC patients who undergo transplant are at particular risk for late pulmonary toxicity and pulmonary fibrosis, which are a known complication of the untransplanted disease. Despite the risks, the best long-term therapy for this patient with DC and progressively falling blood counts is an unrelated donor transplant with appropriately reduced intensity conditioning.

RMS Clinical presentation

Favorable orbit, Non paramenigeal, Paratesties, Vag, Uterus unfavorable Extremities bladder Prostate, Paramenigeal Most common Head and neck LP for Paraspinal paramengeal Lymphnodes checked greater than 10y/o paratesticular or extremities. ERMS low risk T1N0 dont need BM

Glycogen Storage disease type 1

G6P6 and SLC37A4 increase in lactate 1a and 1b clinically identical not on NBS accumlation of glycogen and fat in liver and kidneys doll face, thin limbs, short portruding abdomen 1a: G6Pase activity 1b: G6Pase translocase transporter defecs insufficient conversion of glucose-6-phosphate into glucose through glycogenesis lactic acidosis, hepatomegaly, hypoglycemia 2-4 hours of fasting xanthoma, hyperlipedeima, chronic neutropenia PCOS, low growth, bone disease, renal disease

LAD-2 deficiency

GDP-Fructose transporter 1 Defect in fucosylation of macromolecules of Macromolecules no CD 15 ABO antigens (Bombay phenotype - no H antigen) Sever MR, Short

The IRS group system RMS

Group 1 local disease completely resected Group 2 gross total resection with evidence of regional spread A) margins positive by path not eye B) Margins neg, lymphnodes sampled show disease C Margins positive and nodes show disease Group 3 incomplete resection with gross disease Group 4 Distant Metastatic disease

Costello syndrome

HRAS, AD DD, coarse, cardiomyopathy, pulmonary stenosis RMS

Glucose 6 phosphate catalytic subunit 3 deficiency

Heart defects urogenital anomalies venous angiectasia

A 7-year-old girl with Diamond-Blackfan anemia undergoes stem cell transplantation from her 2-year-old HLA- identical brother. At day 100 neutrophils and platelets are fully reconstituted, but the patient remains red cell transfusion dependent. The marrow reveals red cell aplasia. Genetic analysis reveals 100% donor status. Of the following, what is the most likely cause of this failure of erythroid engraftment? a. Anti-red cell antibodies b. Donor with Diamond-Blackfan mutations c. Graft-versus-host disease (GVHD) d. Inadequate conditioning e. Inadequate cell dose

In matched sibling donor transplants for all forms of inherited bone marrow failure syndromes (IBMFSs), it is essential to critically evaluate the donor for evidence of the same IBMFS. Differences in clinical expression of these disorders may lead to siblings with identical genetic constitutional abnormalities and completely normal or very abnormal blood counts. This requires that the donor be genetically tested for the mutation present in the recipient (if known). In Diamond-Blackfan anemia, evaluation of an erythrocyte adenosine deaminase (eADA) also may be helpful because mutations are known for only about 60% to 75% of clinically diagnosed patients. Anti-red cell antibodies should lead to anemia and hemolysis, not failure of erythroid engraftment. GVHD or inadequate conditioning or cell dose could lead to failure to engraft all cell lines but should not lead to selective erythroid nonengraftment, particularly with a marrow that is 100% donor. The most likely explanation is that the donor also carried the same disease-causing Diamond-Blackfan anemia mutations as the patient, despite the presumably normal pretransplant evaluation including blood counts, which was not apparent to the transplant team, leading to red cell failure to engraft in the recipient.

Beckwith-Wiedemann Syndrome (BWS)

LOH/LOI 11p15 Imprinting; can be caused by maternal chromosomal rearrangements, paternal uniparental disomy, or abnormal methylation; macroglossia, high birth weight and length, umbilical hernia, increased risk of cancer

Chediak-Higashi syndrome

LYST (AR) Albinism, Giant granules, Platelet Defects, HLH impaired phagolysosome formation. Pathophys: Microtubule polymerization disorder means the "tracks" to get around the cell are broken, as such transport of phagosomes is deficient.

G6PD deficiency

Low NADPH leads to hemolytic anemia (free radicals) with bite cells and heinz bodies Fava beans, sulfonamides, primiquine, dapsone X-linked recessive Can alsod develope CGD like disease

monosomy

Myelodysplasia-related cytogenetic features in AML, such as monosomy 5 or del(5q), monosomy 7 or del(7q), or isochromosome 17q, are also associated with inferior outcomes.

Pearson Syndrome (PS)

Neutropenia (Mitochondrial) Vacuolization of erythroid and myeloid precursors, ringed sideroblasts, PEAR Pancytopenia, Exocrine pancreastic insufficiancy, Anemia of siderblastic type Renal tubular acidosis

A 15-year-old girl has had worsening intermittent pain in her right leg for the last few months. She thought she may have injured it when she fell while playing lacrosse. The leg pain is exacerbated by activity, wakes her up at night, and is not alleviated by nonsteroidal anti-inflammatory drugs or rest. She has had no weight loss, fever, breathing difficulty, bruising, nausea/emesis, or pallor. On examination, she is well-appearing, well-perfused, and in no acute distress. There is a firm mass with moderate tenderness to palpation noted at the anterior aspect of her middle thigh, but no adjacent effusion. The remainder of the musculoskeletal and neurologic examination findings are within normal limits. Of the following, which is the most likely diagnosis? Non-ossifying fibroma Chondrosarcoma Osteosarcoma Non-Hodgkin lymphoma of the bone

Osteo Malignant cancers of the bone in pediatrics can be classified as either metastatic from other sources, or primary malignant bone tumors, which are classified by morphologic tumor cell features or by the bone matrix produced by the tumor. Because most benign tumors are asymptomatic, malignant bone cancers frequently present as localized bone pain and swelling, sometimes suspected after minor trauma that highlights the possibility of tumor presence. A thorough physical examination is absolutely necessary in optimizing the diagnosis of bone cancers. Osteosarcoma (OS) is the most common primary malignant bone tumor in pediatric patients and, like many bone tumors, presents as localized pain of several months' duration, especially after trauma or injury. Pain is intermittent, is not relieved by rest, is somewhat more frequent during the day than at night, and is often misdiagnosed as tendinitis. OS presents as a large and tender mass, commonly in the metaphysis of long bones such as the distal femur, proximal tibia, proximal humerus, and other places. Fractures may also be present on x-rays, and classic features of OS on radiographs include indistinct margins, destruction of trabecular bone pattern, and the formation of the classic "Codman triangle," a triangular pattern seen as new periosteal bone formation associated with cortex destruction. The peak incidence of OS in pediatric patients is between 13 and 16 years of age and is more common in boys than in girls.

Noonan Syndrome

PTPN11, SOS1, KRAS, RAF1 (AD) facial features, renal malformation, bleeding disorders Sequencing in the above order. RMS, JMML

Griscelli syndrome type 2

RAB27alpha(AR) Partial Albinism( Siler hair) HLH

Gorlin Syndrome

RMS with the PTCH1 mutation Basal cell nevus syndrome Medulloblastoma Dural calcifications Basal cell skin cancer after radiation Odontogenic keratocysts

Rothmond-Thomson Syndrome

Rash, sparse hair, cataracts , short, skeletal abnormalities,

MLL

Rearrangements involving 11q are common in patients with a monoblastic or myelomonocytic component to their AML. Over 100 rearrangements have been identified, most common partners are KMT2A 11q23.3 and MLLT3 at 9p21.3. They present with DIC, elevated white blood cell count, and leukemic infiltration of the gingiva or skin. The prognostic impact of MLL rearrangements is not entirely clear. Overall survival for pediatric AML appears to be reduced in the presence of MLL rearrangements but the outcomes differ based on the specific translocation partner.

PAX3(7)-FOXO1 fusion?

T(2:13) 60% T(1:13) 20% 20% fusion negative constitutively activated

staging IRS RMS

T1 primary site, T2 external a <5cm, b> 5cm Nodes Stage 1 good site Stage 2 bad site that are small with lymphnode or large without lymphnode Stage 3 bad sites with lymph node involvement Stage for extensive diseae

Barth Syndrome

TAZ, x-linked dilated cardiomyopathy congenital cardiomyopathy underdeveloped skeletal musculature, muscle weakness, short stature, neutropenia

Dyskeratosis congenita (DKC)

Telomerase defect DKC1, TERT,TERT Bone marrow failure nails dystrophy, leukoplakia, hyperpigmented skin

A 10-year-old patient with sickle cell disease type hemoglobin SS has been having severe pain. He has been treated with hydroxyurea but continues to have symptoms of frequent pain requiring hospitalization. Which is the most appropriate next step? a. Add voxelotor if hemoglobin is > 9.5 g/dL. b. Start crizanlizumab-tmca infusions. c. Start L-glutamine. d. Discontinue hydroxyurea and start another agent.

The correct answer is C. Start L-glutamine. L-glutamine would be appropriate for this patient. Crizanlizumab is only FDA approved in children older than 16 years. Use caution with voxelotor at higher hemoglobins until more data are available. The newer agents can and should be used with hydroxyurea.

A 4-year-old boy presents with a diffuse petechial rash (>100 petechiae) and large (>3 cm), diffuse ecchymoses. His labs are remarkable for isolated thrombocytopenia with a platelet count of 3,000 per microliter (mcL). Peripheral smear shows large platelets with normal granulation. His medical history is significant for warm autoimmune hemolytic anemia at 2 years of age. He was treated with steroids and has recovered. He had no recent infection or vaccinations. His exam is notable for the known rash and bruising. His family history is positive for his mother having autoimmune hemolytic anemia as a child, splenomegaly, and diffuse lymphadenopathy. Which of the following blood tests would be most useful in determining the diagnosis? a. Double-negative T cells b. Immunoglobulin G (IgG) c. Antiplatelet antibody d. Vitamin B12

The correct answer is A. Double-negative T cells. The child in the vignette has a presentation of isolated thrombocytopenia, consistent with a diagnosis of immune thrombocytopenia. In the setting of a previous history of autoimmune hemolytic anemia, he now has a diagnosis of Evans Syndrome. In addition, his family history is pertinent with his mother having an immune-mediated cytopenia with physical findings of lymphoproliferation, which is consistent with autoimmune lymphoproliferative syndrome (ALPS). Evans Syndrome is a descriptive diagnosis of patients with multilineage cytopenias. Studies have shown that a large proportion of patients with ALPS, present with Evans Syndrome. In this vignette, the child most likely has a diagnosis of ALPS secondary to an autosomal dominant mutation passed on from his mother. ALPS is recognized as a chronic, recurrent lymphoproliferation with signs of autoimmunity (mostly immune mediated cytopenias) as a consequence of impaired lymphocyte apoptosis. The hallmark of this disease is a high percentage of CD4-CD8- TCRαβ+ T cell or double-negative T cells. This makes A the most useful diagnostic test. Patients with ALPS may also have elevated IgG levels; however, this is not specific to ALPS and can be seen in other autoimmune diseases, so B is incorrect. Similarly, Vitamin B12 levels may be elevated in ALPS, but it is not specific and can be elevated in other diseases (eg, lymphoma, autoinflammatory disease), making D incorrect. Although the patient does have signs of immune thrombocytopenia, antiplatelet antibody testing is not required to make a diagnosis and does not provide diagnostic information specific to ALPS. This makes C incorrect.

Hemophagocytic lymphohistiocytosis (HLH) is an extensive systemic inflammatory response involving lymphocytes and macrophages and associated with an innate cytotoxic defect or inflammasome deregulation. While we must consider HLH as part of a spectrum and a syndrome reflective of many possible underlying etiologies, such as infections, malignances, rheumatologic/autoimmune disease, and inborn errors of immunity, early identification and management of HLH is imperative in order to have an impact on morbidity and mortality. Which of the following is consistent with criteria supportive of a diagnosis of HLH? a. Elevated soluble CD25 (sIL-2Rα) b. Elevated fibrinogen c. Normal CXCL9 d. Decreased IL-18

The correct answer is A. Elevated soluble CD25 (sIL-2Rα). The diagnostic criteria for HLH used in the HLH-2004 trial included having five or more of the eight criteria listed below: 1. Fever > 38.3°C 2. Splenomegaly 3. Cytopenias affecting at least two of three lineages: hemoglobin < 9 g/dL, platelets < 100K per microliter, neutrophils < 1000 per microliter 4. Hypertriglyceridemia (>265 mg/dL) and/or hypofibrinogenemia (<150 mg/dL) 5. Hemophagocytosis in the bone marrow, spleen, liver, or lymph nodes 6. Low or absent natural killer (NK) cell activity 7. Ferritin > 500 ng/mL 8. Elevated soluble CD25 (sIL-2Rα) More current evidence suggests that hemophagocytosis identified within tissues, even in familial HLH, can be a late finding or not seen at all; on the other side, nearly everyone who has active Epstein-Barr virus (EBV) infection will have evidence of hemophagocytosis (without HLH). Therefore, this is not a diagnostic criterion. Additionally, NK cell activity assays can be quite variable and should no longer be included as criteria. Soluble CD25 (sIL-2Rα) will always be elevated in the setting of HLH, but it is not specific for HLH and can be elevated in other circumstances, like infections or sepsis. Further understanding of the underlying processes of HLH has led to additional diagnostic tools, including elevated IL-18 (particularly in macrophage activation syndrome (MAS) and x-linked inhibitor of apoptosis protein (XIAP) deficiency) and elevated CXCL9 (marker of IFN-γ activity). Clinical features and laboratory cytokine markers taken in the context of medical and family history and molecular and genetic testing all aid in the recognition of HLH and thereby diagnosis and management.

A 16-year-old transgender male transitioning to female has a family history of pulmonary embolism in the father at 35 years old. She seeks advice about options for gender-affirming therapies' thrombotic risk. Which of the gender affirming therapies is associated with the highest thrombotic risk? a. Oral estrogen b. Oral spironolactone c. Transdermal estrogen d. Intramuscular leuprolide acetate

The correct answer is A. Oral estrogen. Gender-affirming hormone therapy ameliorates the risk of gender dysphoria, which is commonly experienced by many transgender individuals. In males transitioning to females, these include therapies to achieve physiologic levels of estrogen and/or reduce endogenous testosterone. Both spironolactone and intramuscular leuprolide acetate can reduce testosterone levels and have not been demonstrated to increase thrombotic risk. Transdermal estrogens used at doses for hormone replacement therapy can achieve physiologic levels of estrogen. The thrombosis risk in transgender males transitioning to females treated with transdermal estrogens has been shown to be lower than the thrombotic risk with oral estrogen replacement therapy. Thus, oral estrogen replacement therapy is associated with the highest thrombosis risk.

Regarding equity in academic medicine, which of the following is true? a. There are now equal numbers of male and female students entering medical school. b. There is equity in pay among male and female physicians when correcting for academic rank and subspecialty field. c. There is racial equity in positions of leadership in academic medicine, with equal proportions of Black men in departmental leadership positions compared with White men. d. Sexual harassment is infrequently reported in academic medical centers.

The correct answer is A. There are now equal numbers of male and female students entering medical school. While we have made significant strides toward equity in academic medicine over the last several decades, there remains inequity in several aspects of medical training and practice. It is encouraging that there are now roughly equal numbers of male and female students applying to and being accepted into medical schools across the United States, with some schools reporting a shift toward an increased number of female students entering classes compared with male students. While this is encouraging, women in academic medicine continue to report sexual harassment at an alarmingly high frequency during their clinical rotations, and discrimination or harassment based on race, gender, religion, and sexual orientation remains prevalent. In addition, we see inequity in the advancement of women and racial minorities through the academic ranks, with a disproportionate number of White men achieving the highest academic rank of professor and disproportionately few women and racial minorities achieving this rank. An examination of diversity in leadership positions such as department chairs and medical school deans and associate deans reveals a similar trend, with these positions being held disproportionately by White, non-Hispanic men. Finally, recent studies reveal the persistence of a "pay gap," with men earning a higher salary than women when correcting for academic rank and subspecialty field.

A 14-year-old male presents with fever and a limp. He is found to have a white blood count (WBC) of 85K, hemoglobin of 6.3, and platelet count of 30. Blasts are identified on his peripheral blood smear. A bone marrow biopsy reveals acute lymphoblastic leukemia (ALL). He is risk stratified as high risk based on his presenting WBC. Of note, he is obese with a body mass index (BMI) > 99th percentile for age. Which of the following explains why weight reduction might be beneficial, based on emerging evidence? a. Increased fat content of the bone marrow space is associated with leukemia cell senescence. b. Adipocytes produce enzymes that inactivate daunorubicin. c. Increased BMI is associated with decreased excretion of vincristine. d. Increased BMI is associated with increased neurotoxicity due to intrathecal methotrexate. e. Adipocytes secrete cytokines associated with clonal evolution of leukemic stem cells.

The correct answer is B. Adipocytes produce enzymes that inactivate daunorubicin. An evaluation of data from recent clinical trials reveals an association between obesity and a decreased overall survival in children and adolescents with ALL. Biological factors contributing to this discrepancy in survival are emerging, and the contribution of obesity to both therapeutic toxicity and survival are likely multifactorial. Microscopic examination of the bone marrow reveals that leukemia cells are found tightly associated with adipocytes. Studies reveal that the presence of adipocytes alters the therapeutic effect of both vincristine and daunorubicin in vitro. In vivo studies using obese mice reveal a decreased survival in obese leukemic mice treated with daunorubicin compared with control mice of normal weight. Molecular studies demonstrate that adipocytes metabolize daunorubicin into its inactive metabolite daunorubicinol, and this likely contributes to the decreased chemotherapeutic response in vitro and in vivo. Ongoing clinical trials are examining the impact of weight reduction programs during induction therapy on achievement of negative minimal residual disease assessment at the end of induction therapy in patients with ALL.

You are consulted on an 8-year-old girl with acute lymphoblastic leukemia who is hospitalized with acute SARS- CoV-2 infection. She has a pulmonary infiltrate and is on supplemental oxygen therapy. Which of the following factors would be considered a thrombotic risk in this patient? a. Presence of burr cells on peripheral smear b. Elevated D-dimer activity c. Decreased absolute neutrophil count less than 500/mm3 d. Elevated soluble C5b9 levels

The correct answer is B. Elevated D-dimer activity. Thrombotic risks in this pediatric patient include malignancy, infection, and inflammation. Elevations in the D- dimer have been shown in adult and in some pediatric studies to be associated with thrombotic risk and is the correct answer. The presence of burr cells on a peripheral blood smear has been reported in patients with postinfectious multisystem inflammatory disease (MIS-C). However, burr cells are not associated with thrombosis. Elevated soluble C5b9 levels as well as schistocytes and proteinuria are features of thrombotic microangiopathy (TMA). A high frequency of pediatric patients meets diagnostic criteria for TMA; however, these findings have not been shown to be associated with large vessel thrombosis. Patients with malignancy are at increased risk of hospitalization with SARS-CoV-2 infection. Low absolute neutrophil count is a risk for hospitalization but not for thrombotic complications.

A 2-year-old patient recently diagnosed with acute myeloid leukemia (AML) has started intensive induction chemotherapy therapy with cytarabine, daunorubicin, etoposide, and gemtuzumab at doses that would be expected to cause the patient to be severely neutropenic for more than 7 days. The patient does not have a preexisting history of immune deficiency or history of past bacterial infections. The local antibiogram at their institution does not indicate high resistance to any class of antibiotics. Other than Pneumocystis jirovecii (PJP), what would be the preferred antibacterial prophylaxis strategy? a. No additional antibacterial prophylaxis b. Levofloxacin prophylaxis c. Ceftriaxone prophylaxis d. Cefepime prophylaxis e. Meropenem and vancomycin prophylaxis

The correct answer is B. Levofloxacin prophylaxis. In patients undergoing intensive AML chemotherapy, it has been shown that levofloxacin prophylaxis during intensive chemotherapy cycles notably decreases the likelihood of bacteremia (rate of 21.9% in levofloxacin group versus 43.4% in no-prophylaxis group) in one randomized study. Additionally, an international pediatric- specific antibiotic prophylaxis guideline for children with leukemia recommends levofloxacin prophylaxis for this clinical scenario. There is limited evidence to use other antibiotic agents for prophylaxis even in the setting of increased resistance to levofloxacin. Further investigation is needed to determine the best approach for prophylaxis in the setting of increased resistance. Additionally, there are not sufficient data to recommend antibiotic prophylaxis in pediatric cancer groups that are not receiving intensive chemotherapy.

While on call for the weekend, you receive a call from the emergency department. When referring to a patient with sickle cell disease, the emergency room clinician states, "She says her pain is a 10/10, but she doesn't appear in distress and her vital signs are normal." As the person receiving the call, you have an opportunity to demonstrate your leadership as an anti-racist by doing which of the following? a. Letting the comment go—this is a senior clinician who you know to be a good person. b. Modeling empathy by saying, 'How horrible to have such frequent pain that it becomes normal to you to experience such pain.' c. Modeling empathy by describing how it is typical for patients with sickle cell disease to have stable vitals even in the setting of severe pain. d. Modeling empathy by asking, "Do you think she is not in pain?"

The correct answer is B. Modeling empathy by saying, 'How horrible to have such frequent pain that it becomes normal to you to experience such pain.' Answer A is not an anti-racist response. Answer C is using the "educate" strategy. Answer D. is using the "ask/play dumb" strategy.

In the 1980s, the resource-based relative value scale (RBRVS) was developed to assist in the administration of the Medicare program and was instituted in 1992. The RBRVS establishes a numerical value for relative value units (RVUs) for each Current Procedural Terminology (CPT) code and is broken down into three components. One of these components is the 'physician work RVU' (wRVU). What three activities does the wRVU value encompass? a. Resource cost (which includes physician work), practice expense, and professional liability cost b. Time for physician to perform a service, technical skill and physical effort, and mental effort c. Total RVU, geographic factor, and Medicare conversion factor d. Total RVU, fee schedule, and clinical full-time equivalent (FTE)

The correct answer is B. Time for physician to perform a service, technical skill and physical effort, and mental effort. The listed elements for that answer encompass the physician work effort for any given CPT code. The components included in answer A are the three different components of the total RVU for a given CPT code, not the wRVU specifically. Although the components of answers C and D are certainly elements of the RBRVS system, Medicare reimbursement, and practice administration, they do not specifically address physician work effort under RBRVS.

You are consulting on a hospitalized patient with inflammatory bowel disease (IBD) on the gastroenterology service. There is a question about risk for venous thromboembolism (VTE). Which of the following puts a patient at highest risk for VTE? a. Crohn's disease with active disease b. Ulcerative colitis with active disease c. IBD in the intensive care unit (ICU) d. IBD with poor nutrition e. Ulcerative colitis with gastrointestinal bleeding

The correct answer is B. Ulcerative colitis with active disease. Risk factors for VTE in children with IBD include ulcerative colitis (higher risk than Crohn's disease), hospitalization, active disease, and a central venous catheter. Poor nutrition, gastrointestinal bleeding, and ICU stays are not independent risk factors.

The parents of a 4-year-old with relapsed acute myeloid leukemia (AML) come to see you for a second opinion. The child has experienced AML relapse after stem cell transplantation but has not yet begun a course of reinduction therapy post relapse. The parents have heard about the success of chimeric antigen receptor (CAR) therapy for acute lymphoblastic leukemia and are seeking your guidance on the potential for AML CAR therapy. Which of the following is the most appropriate recommendation to provide to the family? a. Their child is not eligible as all AML CAR trials require patients to be in second or greater relapse. b. They should seek out a natural killer (NK) cell CAR trial as randomized clinical trials have shown NK cell CARs to be superior to T-cell CARs. c. Current AML CAR trial options include several cell surface proteins such as CD123 and CD33. d. Treatment with a standard AML reinduction regimen would be required prior to enrollment in any AML CAR trial.

The correct answer is C. Current AML CAR trial options include several cell surface proteins such as CD123 and CD33. Current AML CAR trials target CD123 and CD33 with several other trials targeting other cell surface proteins in development. AML CAR trials typically require a second or greater relapse only for patients who have not received a stem cell transplant. While the NK cell CAR data are very promising, there are no randomized clinical trials comparing NK and T-cell CARs. AML CAR trials do not require pretreatment with a reinduction regimen for eligible patients and intensive AML reinduction therapies may result in complications delaying clinical trial enrollment.

A 13-year-old female with newly diagnosed localized osteosarcoma of the right femur is seen for a treatment discussion. She and her parents have questions about the long-term effects of chemotherapy, particularly the impact on fertility. Of the following, which is the most likely agent to impact her future fertility? a. Doxorubicin b. Etoposide c. Ifosfamide d. Methotrexate

The correct answer is C. Ifosfamide. Many chemotherapy agents have both short- and long-term toxicity. Of the agents listed for treatment of osteosarcoma, the agent most likely to impact fertility is ifosfamide. This toxicity is cumulative, and females may experience premature ovarian failure and resultant infertility. In general, prepubertal status in females may provide some protection. The American Society of Clinical Oncology (ASCO), American Society for Reproductive Medicine (ASRM), American Academy of Pediatrics (AAP), and American College of Obstetricians and Gynecologists (ACOG) all recommend a patient-centered discussion about the gonadotoxic effects of cancer treatment and options for fertility preservation prior to initiation of therapy for all patients.

A 14-year-old male presented with 4 months of left neck swelling. He denies any night sweats, fevers, or weight loss. He had an excisional biopsy performed that demonstrated pediatric-type follicular lymphoma (PTFL). Which is true regarding the pathology for this malignancy? a. It is BCL6 negative. b. It has a low proliferative index. c. It is BCL6 positive. d. It demonstrates t(14;18)(q32;q21).

The correct answer is C. It is BCL6 positive. PTFL was recognized as a World Health Organization (WHO) diagnostic entity in 2016, distinct from follicular lymphoma (FL). The pathology demonstrates effacement of nodal architecture with pure follicular proliferation. It is BCL6 positive and BCL2 negative with a high proliferation index. There notably is absence of the adult follicular lymphoma gene rearrangements including t(14;18)(q32;q21). There are no BCL2, BCL6, MYC, or IRF4 rearrangements. The mitogen-activated protein kinase (MAPK) pathway is important in pathogenesis. MAP2K1 mutations are present in 43% of cases. PTFL is an indolent malignancy that presents in males more than females and often is localized to the head and neck. By WHO definition, there must be nodal, localized disease (stage I/II). Unlike adult conventional FL, it does not transform to diffuse large B-cell lymphoma and does not have a relapsing/remitting course. It is a rare lymphoma and thus there are no randomized controlled trials. Case reports and small series have demonstrated long-term survival of >95% with surgery alone or with multiagent chemotherapy with or without anti-CD20 directed therapy.

You have an upcoming faculty meeting where you will be introducing your program and your research interests. You hope to use that time to gracefully self-promote your recent accomplishments to your department of pediatrics. What are the key components of a 'PAR' statement to help succinctly express your achievements? a. Promote, achieve, respond b. Problem, analysis, result c. Problem, action, result d. Promote, action, respond

The correct answer is C. Problem, action, result. Graceful self-promotion is a way of speaking diplomatically and strategically about yourself and your accomplishments. Using a PAR statement can help you more succinctly express your achievements and showcase your accomplishments and the impact of your work. Problem: What was the problem you had to solve? (One sentence) Action: How did you address or solve it? (One sentence demonstrating your attributes/skills) Result: What happened? (One sentence; be specific and quantitative.)

A 10-year-old girl presents to the emergency department with a 3-week history of headaches and progressive vomiting. A head computed tomography (CT) reveals a posterior fossa mass, which is subsequently further characterized by magnetic resonance imaging (MRI). The child undergoes a complete surgical resection of the tumor and is diagnosed with a sonic hedgehog (SHH), TP53-wild type medulloblastoma. The patient does not have metastatic disease. The patient also is enrolled in a biology study and both tumor tissue and peripheral blood are submitted for paired tumor/germline sequencing. No somatic or germline alterations are reported. There are currently no open clinical trials for your patient, and you begin to discuss standard of care treatment with the family. Which of the following statements is true? a. SHH, TP53-wild type medulloblastoma has a poor prognosis and early involvement of palliative care is indicated. b. This patient should be given treatment with vismodegib during radiation therapy. c. SHH subgrouping is based on the DNA methylation profile of the tumor. d. The patient does not have a cancer predisposition syndrome because the germline results were negative. e. The child has a favorable prognosis and reduction in craniospinal irradiation (CSI) therapy is appropriate due to significant late effects of CSI.

The correct answer is C. SHH subgrouping is based on the DNA methylation profile of the tumor. Answer A is incorrect because TP53-wild type SHH medulloblastoma has a good prognosis. The TP53 mutated tumors have a poor prognosis. Answer B is incorrect because insufficient information was provided in the clinical vignette to suggest that this patient would benefit from the addition of the targeted therapy agent and no data exist to suggest that combining vismodegib with radiation therapy is beneficial. Answer C is the correct answer because the SHH group is one of the four subgroups identified by DNA methylation profiling in addition to WNT, Group 3 and Group 4. Answer D is incorrect because patients with cancer may still have a germline cancer predisposition syndrome even with negative genetic testing. This may be due to a limit in the number of genes or exons that are sequenced, the coverage, or the practice of the lab for reporting novel variants or variants of uncertain significance. Answer E is incorrect because it is not standard of care to reduce craniospinal radiation therapy outside of a clinical trial.

A 12-year-old patient who is being treated for acute lymphoblastic leukemia has a platelet count of 7000 ul/mcl and is currently receiving a unit of platelets. What features of platelet production and storage lead to their historically higher rates of infectious transmission? a. Storage at 1°C-6°C b. Saline-based suspension c. Storage at 20°C-24°C d. 10-day shelf life

The correct answer is C. Storage at 20°C-24°C. The other answers are all incorrect regarding the storage and production of platelets. Platelets are not stored at 1°C-6°C; they are stored at room temperature (20°C-24°C). Platelets are produced and stored in a plasma-based suspension, not a saline-based suspension. The maximum FDA-approved shelf life for platelets is 7 days with additional testing, while the standard FDA shelf life of platelets is 5 days; platelets are not approved to have a 10-day shelf life.

An 11-year-old boy who was previously diagnosed with precursor B-cell acute lymphoblastic leukemia (ALL) now has bone marrow (BM) recurrence after completing therapy. When discussing the possible treatment options with his parents, which of the following is true of chimeric antigen receptor (CAR) T-cell therapy? a. Tisagenlecleucel (Kymriah) is currently approved for children with first relapse of ALL. b. Tisagenlecleucel should be considered for this patient only if he also has extramedullary disease. c. Tisagenlecleucel should be considered if disease is refractory to initial therapy for relapse. d. Tisagenlecleucel is contraindicated in children who have received prior treatment with blinatumomab.

The correct answer is C. Tisagenlecleucel should be considered if disease is refractory to initial therapy for relapse. Tisagenlecleucel is currently FDA approved for children with refractory disease or second or greater relapse. A is incorrect as tisagenlecleucel is not yet approved for first relapse in the absence of refractory disease. B is incorrect as tisagenlecleucel has been shown to be effective for both BM and extramedullary (central nervous system) disease. D is incorrect because patients with blinatumomab can receive tisagenlecleucel. There is some concern about CD19 downregulation/escape, but this is a consideration and not a contraindication.

Brad is an 11-year-old male with recurrent osteosarcoma. His disease has proven refractory to many lines of chemotherapy, and you are meeting with the family to discuss a potential phase 1 clinical trial. To best assist this family with the decision of participating in an experimental trial, you are planning to rely on your skills for shared medical decision making. When facilitating shared medical decision making with patients and families, which of the following should one consider? a. The current medical information, including available treatment options b. What is important to the patient and family c. Offering recommendations that align with the patient's and family's goals d. All of the above e. None of the above

The correct answer is D. All of the above. Shared decision making (SDM) has been defined as "an approach where clinicians and patients share the best available evidence when faced with the task of making decisions, and where patients are supported to consider options, to achieve informed preferences" (1). It involves the clinician sharing pertinent medical information, including possible therapeutic options, as the primary step and assessing patient/family understanding. This is followed by exploration of patient and family goals and allowing space for deliberation of the medical options. Physicians should offer support as the patient and family explore these options and suggest recommendations after first eliciting permission to do so. Recommendations should be offered in the context of patient- and family- specific goals. SDM recognizes the need to support autonomy by building good relationships, respecting both individual competence and interdependence on others. References: 1. Elwyn G, Coulter A, Laitner S, Walker E, Watson P, Thomson R. Implementing shared decision making in the NHS. BMJ. 2010;341:c5146. doi:10.1136/bmj.c5146.

An investigator wishes to do a study using the Pediatric Health Information System (PHIS) database to assess patterns of hospital admissions and medication utilization for pediatric cancer patients who present with seizure. Which data points would not be available in the PHIS database? a. Cancer diagnosis codes b. Seizure diagnosis codes c. Seizure medications ordered and given in the hospital d. Description of the seizure given by the ER attending physician in the progress note e. Whether an electroencephalogram (EEG) procedure was performed

The correct answer is D. Description of the seizure given by the ER attending physician in the progress note. PHIS is a de-identified database with clinical and resource utilization data for inpatient, ambulatory surgery center, emergency department, and observation unit encounters. It represents approximately 25% of the pediatric centers in the United States, but most are pediatric tertiary care centers. Although PHIS is a robust database that contains specific information like diagnosis codes, medications given inpatient, and procedure codes, it unfortunately does not contain specific information from medical progress notes.

A previously healthy 10-year-old boy presents with a slowly growing mass in the right lower extremity. Magnetic resonance imaging (MRI) reveals a heterogeneous, lobulated mass intermixed within the skeletal muscle of the posterior thigh. He undergoes an interventional radiology-guided core needle biopsy and pathology is most suggestive of desmoid tumor with positive immunohistochemical staining for nuclear beta-catenin. Sequencing for a beta-catenin mutation is performed and is negative. As part of the continued workup for this patient, which of the following should be performed? a. Methylation analysis b. Whole-body MRI c. Ophthalmology evaluation d. Germline testing for an adenomatous polyposis coli (APC) gene mutation e. Wood lamp (light) examination

The correct answer is D. Germline testing for an adenomatous polyposis coli (APC) gene mutation. Approximately 80%-85% of desmoid tumors have beta-catenin or APC mutations, with the majority having somatic mutations of beta-catenin. The finding of a somatic beta-catenin mutation helps exclude a syndromic condition. Absence of a beta-catenin mutation should raise suspicion for familial adenomatous polyposis or Gardner syndrome, especially in children. Thus, it is recommended that those patients with an absent somatic beta-catenin mutation undergo further evaluation with germline testing for an APC mutation due to the impact on the affected patient and other family members.

A pediatric hematologist/oncologist is working on her dossier/academic portfolio for promotion to clinical associate professor on the clinical educator track. This person is very active on social media in a professional capacity. She decides to list all her professional educational activities on social media platforms under the category of nontraditional activities. Which of the following should not be included? a. Podcasts b. Online or blog articles c. Tweetorials and educational tools d. Online journal clubs and chats e. Speaker invitation to a grand round

The correct answer is E. Speaker invitation to a grand round. Speaking invitations to conferences, grand rounds, international healthcare organizations, and government agencies are activities that fulfill the traditional criteria for promotion at academic centers. Digital/social media scholarship that is original and advances the field of health professions education is increasingly being recognized as a nontraditional activity that can fulfill criteria for promotion at several academic centers.

t(9;22)

The latest WHO classification includes 2 provisional entities: AML with t(9;22); BCR-ABL1 (rare but may benefit from treatment with tyrosine kinase inhibitors)

FLT3-ITD mutations

The t(6;9) mutation in AML is associated with basophilia, pancytopenia, and marrow dysplasia. About 70% of cases have FLT3-ITD mutations, and this subtype is associated with an unfavorable prognosis. Abnormalities of 3q in AML are associated with thrombocytosis and atypical megakaryocytes in the bone marrow. The t(1;22) mutation in AML usually involves the megakaryoblastic lineage and occurs more commonly in infants.

An 8-year-old girl with severe aplastic anemia is transfusion dependent for red cells and platelets and has an ANC of 450/μL. Workups for Fanconi anemia and infectious causes of bone marrow failure are negative. She is here today with her parents and two siblings, one of whom is HLA compatible. What would you suggest as the next step in management of this patient? a. Acyclovir therapy of viral marrow suppression b. GCSF at the lowest dosage and frequency possible c. Hematopoietic stem cell transplant (HSCT) from sibling donor d. Immunosuppressive therapy e. Oral androgen therapy

The treatment of choice for severe aplastic anemia (SAA) in childhood is an HLA-matched sibling donor hematopoietic stem cell transplant (HSCT). All patients with SAA should be HLA typed at diagnosis, and all full siblings also evaluated. If a compatible sibling donor is available, then transplant should proceed as soon as possible. If a sibling donor is not available, then registries should be queried to determine if an acceptable unrelated donor (URD) might be readily available as URD transplant is under investigation as first-line therapy, but current recommendations are to promptly proceed to immunosuppressive therapy (IST) as first treatment. If there is not an adequate response to IST within 3 to 6 months (generally transfusion independence at a minimum), then unrelated donor transplantation (if a donor can be identified) or retreatment with IST should be pursued. After IST, blood counts often remain abnormal, albeit improved to levels of transfusion independence, but there is an ongoing risk of relapse or clonal evolution. Short-term survival with sibling donor HSCT and IST are comparable, but long-term outcomes and the quality of count recovery are superior with sibling donor HSCT. Current research trials are investigating the feasibility of progressing to URD HSCT as initial therapy and comparing that to IST for patients without an upfront sibling donor. This patient has no evidence of a viral cause of her aplastic anemia, so acyclovir therapy is not indicated and may be marrow suppressive. Randomized trials with granulocyte-colony stimulating factor did not show an improvement in outcome for SAA patients, and indeed this may promote the development of myelodysplasia. Oral androgen therapy is utilized in the management of Fanconi anemia in patients without acceptable donors and does not have a role in SAA.

A 5-week-old male infant has an unremarkable medical history. His examination findings are notable only for a hemangioma on the tip of his nose that is 5 mm in diameter. His parents state that it appeared over the past week and seems to be growing rapidly. In addition to referring to a hemangioma specialist, which of the following is the most appropriate treatment for this child's lesion? a Topical clobetasol b Topical timolol c Oral prednisolone d Oral propranolol

This child has an infantile hemangioma (IH), which is a benign neoplasm of vascular epithelium and one of the most common tumors of childhood, occurring in about 4% to 5% of infants. They are more common in female, twin, preterm, and low-birthweight infants. Typically, they are not present at birth. Shortly after birth, subtle skin findings can develop, such as telangiectasias, erythematous macules, or blanched spots that can represent an indicator of where the tumors will grow. The majority of IHs are low risk and require observation, but no active intervention is needed other than monitoring and parental education. Rarely, IHs are classified as high risk if there is evidence of, or potential for, life-threatening complications; functional impairment or ulceration; associated structural anomalies; or permanent disfigurement. These require rapid evaluation and management by a hemangioma specialist. The tip of the nose, the pinna, and the lip are areas where there is a risk of disfigurement or permanent distortion of anatomic landmarks if the IH is left untreated. Oral propranolol is the first-line treatment for IHs that require intervention. Oral corticosteroids were formerly the first-line treatment for IHs but are no longer recommended due to their high side effect profile. Topical timolol is indicated for the treatment of thin or superficial IHs, but not one on the tip of the nose, which is associated with increased risk of permanent disfigurement. Topical clobetasol is not indicated in the treatment of IH.

An 8-month-old, gastrostomy-tube dependent, ex-premature infant is referred with WBC of 5,000/mm3, ANC 650/mm3, hemoglobin 10.8 g/dL, mean corpuscular volume (MCV) 100 fL, and platelet count of 200,000/mm3/L. Prothrombin time (PT) is slightly prolonged, but partial thromboplastin time (PTT) and fibrinogen are normal. Serum B12 and folate, liver enzymes, and bilirubin levels are normal. She has chronic smelly diarrhea and is growing slowly despite adequate caloric intake. There is no history of fever or infections either in the stool or systemically. A sweat chloride test for cystic fibrosis and workup for celiac disease are negative. A mutation in which gene might account for the constellation of symptoms in this child? a. c-Mpl b. ELA2 c. RPS19 d. SAMD9 e. SBDS

This child has moderate neutropenia without a history of infection, mild anemia with macrocytosis but normal B12 and folate, and a normal platelet count. While this could all be reactive to the gastrointestinal process and a consequence of prematurity, failure to thrive, steatorrhea, and the elevated PT most likely related to vitamin K deficiency are consistent with fat malabsorption. The combination of exocrine pancreatic insufficiency and otherwise idiopathic neutropenia is strongly suggestive of Shwachman-Diamond syndrome, associated with mutations in the SBDS gene in the vast majority of cases. Mutations in c-Mpl are associated with congenital amegakaryocytic thrombocytopenia and clinical thrombocytopenia, which is not present here. ELA2 mutations are associated with severe congenital neutropenia (SCN) or cyclic neutropenia (CN), and chronic diarrhea due to exocrine pancreatic insufficiency is not characteristic of either SCN or CN. RPS19 mutations are associated with Diamond-Blackfan anemia, in which neutropenia may occur, but this disorder generally presents with macrocytic red cell aplasia without malabsorption secondary to pancreatic insufficiency. SAMD9 mutations are associated with immunodeficiency and adrenal insufficiency rather than pancreatic issues.

A 5-year-old girl with a previously normal CBC now presents in your office with a hemoglobin of 8.5 g/dL, corrected reticulocyte count of 0.1%, and mean corpuscular volume of 80 fl. White cells and platelets are normal in number and morphology. Bilirubin, LDH, BUN, creatinine, and urinalysis are normal. Direct and indirect antiglobulin tests are negative. Workup for infection, including parvovirus, is negative. Occult blood in her stools is negative. Physical examination is unremarkable. She has had no restriction in her energy or activities and the family agrees she is "fine." What is the most appropriate next step in management? a. Administer erythropoietin. b. Initiate a red cell transfusion. c. Observe serial hemoglobin values closely . d. Prescribe oral iron supplement. e. Send red cell adenosine deaminase (eADA).

This patient has normocytic red cell aplasia, the most common causes of which are Diamond-Blackfan anemia (DBA) and transient erythroblastopenia of childhood (TEC). DBA, which is often associated with an elevated erythrocyte adenosine deaminase level, typically presents in infancy with macrocytic red cell aplasia but may present in adulthood with normalization of the mean corpuscular volume (MCV) for age. TEC typically presents at an older age than DBA, and the MCV is typically normal. In an asymptomatic patient, transfusion may be deferred at this hemoglobin level. Thus, this patient is most likely to have TEC, and close clinical observation of her blood counts (and clinical status) for the need for a transfusion is the indicated management. An eADA may help to clarify your thinking that this is TEC, but likely, by the time you have the result, blood counts will have recovered and it will be unnecessary. Close observation will still be required. Erythropoietin levels are typically already high with red cell aplasia, and additional exogenous dosing is not beneficial. Although she is anemic, the MCV does not demonstrate microcytosis, which should predate the anemia if the cause were iron insufficient hematopoiesis.

WHIM syndrome

WARTY HYPOS DOMINATED our GAME of GLOBAL INFECTION by NEUTRALIZING my soldiers BONES with CXCR4 guns. Warts Hypogammaglobulinemia Infections Myelokathesis - neutropenia due to retention of neutrophils in bones Mutated Chemokine receptor CXCR4 gene

IgA deficiency

What antibody deficiency is associated with transfusion related anaphylaxis?

LAD-1 (Leukocyte Adhesion Deficiency)

What disease occurs due to defective leukocyte adhesion and migration linked to decreased or absent expression of B2 integrins? Absent decrease CD18 expression

Li-Fraumeni syndrome

a condition caused by a germline mutation in tumor suppressor gene p53;

Genetics that define AML

are diagnostic of AML, regardless of bone marrow blast count are: t(6:9)DEK-NUP214 t(15;17); PML-RARA t(8;21); RUNX1-RUNX1T1 inv(16) or t(16;16); CBFB-MYH11 NEW to the seen Inv 3 GATA2 MECOM Megakaryblastic t(1;22)RBM15-MKL1 Mut NPM1 Biallelic mut CEBPA

May-Hegglin Anomaly

autosomal dominant inherited blood cell disorder characterized by thrombocytopenia and granules containing cytoplasmic inclusions similar to Dohle bodies

Hermansky-Pudlak syndrome type 2

autosomal recessive AP3P1 disorder comprising oculocutaneous albinism, platelet dysfunction, and immunodeficiency arising from neutropenia and T-lymphocyte dysfunction.

Chronic Granulomatous Disease (CGD)

defect in NADPH oxidase → ↑ susceptibility to infections with catalase + organisms (S. aureus, Aspergillus, etc...) Abscess really common Burkholderia Diagnosis 123DHR, or WES

Schwachman-Diamond syndrome

exocrine pancreatic insufficeincy (chronic diarrhea), short stature, (metaphyseal chondroplasia) neutropenia, Bone abnormlaities

Gaucher disease

glucocerebrosidase (β-glucosidase) def. → ↑ glucocerebroside *aseptic necrosis of femur*, Gaucher cells (lipid-laden Mφ's, crumpled tissue paper), hepatosplenomegaly Bone marrow failure delayed finding

Acute Promyelocytic Leukemia (AML M3)

leukemia is characterized by t(15;17), which results in a PML-RARA fusion gene. Balanced translocation Acute promyelocytic leukemia frequently presents with disseminated intravascular coagulation and has a high early mortality risk, but prompt institution of all-trans retinoic acid and supportive care for the coagulopathy can result in excellent survival. The malignant cells have a characteristic morphologic appearance with a nucleus that may be folded, reniform, or bilobed. Coarse azurophilic granules and Auer rods are usually present. The unique clinical presentation of APL is characterized by promyelocytic infiltration of the bone marrow, disseminated intravascular coagulation (DIC), and fibrinolysis. The PML-RARA fusion gene that occurs as a result of this translocation contains most of the coding sequences of the promyelocytic leukemia gene (PML) and the DNA binding/ligand-binding domains of the α-retinoic acid receptor gene (RARA). The fusion protein has decreased sensitivity to retinoic acid, which may lead to persistent transcriptional repression and prevention of promyelocyte differentiation.

undifferentiated Sarcoma

most common NRST (no question here)

inv(16) or t(16;16)

mutation in AML is often associated with abnormal eosinophils in the bone marrow and a favorable response to conventional AML chemotherapy. It can also present as an extramedullary myeloid sarcoma. This cytogenetic abnormality results in the juxtaposition of the myosin, heavy chain 11, smooth muscle gene (MYH11) and the core-binding factor, B subunit gene (CBFB).

ALPS (autoimmune lymphoproliferative syndrome)

mutation in Fas gene, autoimmune cytopenia, Elevated B12, splenomegaly, lymphadenopathy

Neutrophil maturation sequence

myeloblast, promyelocyte, myelocyte, metamyelocyte, band, seg

Infantile fibrosarcoma

t(12;15)(p13;q25) ETV6(TEL)-NTRK3 Larotrectinib

Synovial sarcoma translocation

t(X;18) > 90% of cases; SYT(18)-SSX(X). Translocation predicts more nodal spread.56% response rate to chemo

GATA-2

transcription factor required for the development of all hematopoietic lineages