Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, life-threatening hematologic stem cell disorder characterized by hemoglobinuria, thrombosis, and tendency for bone marrow failure. The rare incidence of PNH in children, its nonspecific clinical presentation, and occasional absence of hemoglobinuria make the diagnosis challenging. We present a case of a 17-year-old boy who was hospitalized with a history of recurrent abdominal pain, fever, and dark-colored urine. Laboratory tests revealed anemia, thrombocytopenia, and elevated inflammatory markers. Urinalysis was positive for protein and red blood cells, too many to be counted. Complement studies were within normal limits. Abdominal computed tomography showed a segment of the small bowel with wall thickening and signs of possible microperforation. Exploratory laparotomy revealed necrosis of the small bowel, and histological evaluation was suggestive of an autoimmune process with small vessel vasculitis. Bone marrow biopsy showed hypocellular marrow with a decreased number of myeloid cells, normal number of megakaryocytes, and signs of erythroid hyperplasia. Flow cytometry detected deficiency of CD59 leading to the diagnosis of PNH. The patient was treated with eculizumab infusions resulting in significant improvement. This case highlights the need for high clinical suspicion for rare entities such as PNH in patients presenting without hemoglobinuria.
Background: Chromosomal translocations leading to MLL chimeric oncoproteins are the primary aberrations in infant acute leukemias, but how these translocations are created has not been established. A Children’s Oncology Group population epidemiology study recently validated that maternal consumption of dietary items containing topoisomerase II interacting compounds during pregnancy increases the risk of infant AML with MLL translocations. An inactivating polymorphism in the gene encoding NQO1, which detoxifies the topoisomerase II poison p-benzoquinone, also is associated with an increased risk of MLL-rearranged acute leukemias in infants, with the greatest risk for cases with t(4;11). Although there is heterogeneity, it has been suggested that infant leukemias share the same biased MLL translocation breakpoint distribution 3′ in the breakpoint cluster region (bcr) as secondary leukemias arising following chemotherapeutic topoisomerase II poisons. These observations led us to investigate the relationship between topoisomerase II cleavage complexes induced by dietary substances or p-benzoquinone and translocation breakpoints 3′ in the bcr. Methods: Southern blot analysis was used to identify the MLL rearrangement in the AML of an infant male harboring the inactivating NQO1 polymorphism, and the MLL-AF9 genomic breakpoint junction was characterized by panhandle variant PCR. DNA substrates containing the normal homologues of the breakpoint sequences were utilized in topoisomerase II in vitro cleavage assays in the presence of p-benzoquinone or dietary substances to determine whether topoisomerase II cleavage sites were stimulated by these agents at the observed translocation breakpoints. Results: There was a single MLL bcr rearrangement in the infant AML, and the cloning demonstrated a breakpoint junction fusing MLL bcr position 6774, 6775, 6776, 6777, 6778, 6779, 6780 or 6781 in intron 8 to position 35940, 35941, 35942, 35943, 35944, 35945, 35946 or 35947 relative to the start of AF9 intron 5. Identical 5′-GTTCTTA-3′ sequences suggesting the DNA double strand break repair mechanism of NHEJ were present at both breakpoints. The normal homologues of the breakpoints in MLL and AF9 were reciprocally cleaved by topoisomerase II in the presence of p-benzoquinone, and the cleavage sites were resolved to form the breakpoint junction. The MLL substrate contained another topoisomerase II cleavage site at position 6760 that not only was the strongest cleavage site in this substrate with the enzyme alone, but also was enhanced by p-benzoquinone, genistein, genistin, quercitin, and catechin at levels comparable to or greater than the anticancer drug etoposide. Further analysis of 3′ MLL bcr substrates revealed cleavage stimulation by natural topoisomerase II poisons near additional translocation breakpoints. Conclusions: These results establish the relationship between topoisomerase II mediated damage from p-benzoquinone and dietary exposures and MLL translocation breakpoints. MLL translocation breakpoints in infant leukemias can be explained by topoisomerase II cleavage. The combined evidence from population epidemiology studies on maternal-fetal exposures, the NQO1-leukemia association implicating p-benzoquinone, genomic breakpoint junction cloning and topoisomerase II cleavage assays corroborate that topoisomerase II poisons damage MLL in acute leukemia in infants.
Introduction: Patients with birth defects have a higher incidence of cancer; however, an association of amniotic band syndrome (vascular disruption syndrome) with congenital leukemia has never been reported. We characterized a case of MLL-rearranged leukemia in a neonate affected with this birth defect. Methods: The MLL translocation was characterized in peripheral AML blasts by karyotype analysis, multicolor FISH, Southern blot analysis and genomic and cDNA panhandle PCR. NQO1 genotype was determined by real-time PCR. Clinical history and results: The infant was born at 38 weeks gestation by C-section for suboccipital encephalocele to a 21 year-old gravida 3 para 2 mother with a history of cigarette, marijuana, cocaine and opiate use, and antidepressant, antipsychotic, barbiturate, caffeine and proton pump inhibitor treatment during pregnancy. Drug screen at delivery was positive for opioids and barbiturates. In addition to the encephalocele, a circular constriction of the right arm, consistent with amniotic band syndrome, and blueberry muffin lesions were noted at delivery. The CBC showed mild thrombocytopenia that resolved the next day. Congenital infection was excluded. The encephalocele was repaired. At 19–20 days of age the infant became septic and hepatosplenomegaly and hyperleukocytosis were observed. The peripheral smear and flow cytomery revealed acute myeloid leukemia with monocytic differentiation (CD45+ population positive for CD4, CD14, CD33, CD38, HLA-DR). Karyotype analysis showed a complex structural abnormality disrupting chromosomes 4, 11 and 19 involving MLL. M-FISH showed insertion of chromosome 11 material into a chromosome 19 and translocation between chromosomes 11q and 4q. The infant received cytosine arabinoside and daunomycin but succumbed to AML, sepsis and multi-organ failure within 4 days. Autopsy showed marrow, viscera, brain and skin infiltration with AML and Chiari type III brain malformation. Southern blot analysis detected two MLL bcr rearrangements. Panhandle PCR demonstrated fusion of MLL intron 6 and intron 1 of ELL from band 19p13.1. Short sequence homologies at the breakpoint junction suggested DNA damage resolution by NHEJ repair. The corresponding transcript joined MLL exon 6 to ELL exon 2. The infant was wild-type at NQO1 C609T. Conclusions: This is the first association of amniotic band syndrome and congenital AML, both of which are rare conditions. Although the cause(s) are unknown, both conditions originate in utero and maternal exposures during pregnancy may be relevant. There was a history of maternal fetal loss, which is a risk factor for leukemia in infants. The NQO1 substrate p-benzoquinone in cigarette smoke is a topoisomerase II poison, but the infant did not harbor the NQO1 variant that predisposes to leukemia. Cocaine is an in utero exposure implicated in amniotic band syndrome. The occurrence of amniotic band syndrome and congenital AML in this infant raises questions about potential host predisposition or gene-environment interactions common to both conditions. Alternatively, both rare conditions may have occurred by chance alone in the setting of the many in utero exposures.
ImportanceLittle is known about the risk of post–COVID-19 multisystem inflammatory syndrome in children (MIS-C) in the setting of childhood cancer.ObjectiveTo evaluate factors associated with MIS-C and describe the clinical course of COVID-19 in the setting of MIS-C.Design, Setting, and ParticipantsMultisite observational cohort study of a registry representing more than 100 US pediatric oncology sites. All included patients were registered between April 1, 2020, and May 18, 2022. Sites submitted deidentified data surrounding sociodemographics, cancer diagnosis and treatment, and COVID-19 course (symptoms, maximum support required, outcome). Patients with MIS-C (n = 24) were compared with matched controls (n = 96). Children (<21 years) with cancer who developed COVID-19 while receiving cancer treatment or within 1 year of completing treatment were characterized based on their development of MIS-C.Exposures(1) Clinical and sociodemographic characteristics of children with cancer and COVID-19; and (2) MIS-C.Main Outcomes and Measures(1) Development of MIS-C among children with cancer and COVID-19; and (2) symptoms and disease severity associated with MIS-C.ResultsAmong 2035 children with cancer and COVID-19, 24 (1.2%) developed MIS-C. COVID-19 occurred at a median (IQR) age of 12.5 (5.5-17.1) years in those with MIS-C and 11 (6-16) years among matched controls (P = .86). The majority of children with MIS-C had a hematologic cancer (83.3% [n = 20]), were publicly insured (66.7% [n = 16]), and were Hispanic (54.2% [n = 13]). Half (n = 12) had 1 or more noncancer comorbidity. Those with comorbidities were more likely to develop MIS-C than those without (odds ratio [OR], 2.5 [95% CI, 1.1-5.7]). Among children with MIS-C, 100% (n = 24) were admitted to the hospital and 54.2% (n = 13) to the intensive care unit (ICU), while COVID-19 contributed to the death of 20.1% (n = 5); cancer therapy was changed in 62.5% (n = 15). Compared with matched controls, those with MIS-C had higher odds of symptoms classified as systemic (OR, 4.7 [95% CI, 1.4-15.8]) or gastrointestinal (OR, 5.0 [95% CI, 1.7-14.6]) along with higher odds of hospitalization (OR, 42.9 [95% CI, 7.1-258]), ICU admission (OR, 11.4 [95% CI, 3.6-36.4]), and changes to cancer therapy (OR, 24.9 [95% CI, 6.5-94.8]).Conclusions and RelevanceIn this cohort study among children with cancer and COVID-19, those with MIS-C had a more severe clinical course than those without MIS-C. The risk of MIS-C and its severity are important to consider as clinicians monitor patients with COVID-19. These findings can inform their conversations with families regarding COVID-19 risks and the benefits of prevention strategies that are pharmacologic (vaccination) and nonpharmacologic (masking), as well as treatment (antivirals, monoclonal antibodies).
Background: Imatinib has become standard front-line therapy for CML. In ~3% of patients treated with imatinib, abnormalities including trisomy 8 and/or monosomy 7 occur in Ph’ negative subclones and dysplasia occasionally is present, but transformation to AML is rare. We describe the first known case of AML with an MLL translocation during an imatinib-induced molecular remission of CML. Methods: The Ph’ and the t(11;19)(q23;p13.1) were detected and monitored in sequential marrows using cytogenetic and FISH analyses. The BCR-ABL1 fusion transcript was traced by RT-PCR. The MLL translocation was identified and characterized in the AML blasts by Southern blot analysis, panhandle PCR-based methods and conventional PCR. Clinical History and Results: The patient presented with chronic phase CML at age 53 and was treated with hydroxyurea for 6 weeks, IFN-α for 20 months and imatinib for 32 months. Complete cytogenetic response was achieved at 10 months. Molecular remission, as indicated by absence of the BCR-ABL1 transcript, occurred after 15 months of imatinib (37 months from CML diagnosis). Mild dysgranulopoiesis was noted 6 months after imatinib was started and increased on subsequent studies. After 28 months of imatinib (50 months from CML diagnosis), there was marked trilineage dysplasia and the karyotype showed t(11;19)(q23;p13.1) in cells that were Ph’ negative and negative for the BCR-ABL1 fusion transcript. FAB M5b AML was diagnosed four months later. The patient succumbed to AML despite aggressive management with chemotherapy and allogeneic stem cell transplantation. Southern blot analysis of the AML revealed two MLL bcr rearrangements. The reciprocal breakpoint junctions on the der (11) and der (19) chromosomes indicated a translocation of intron 8 of MLL and intron 1 of the known MLL partner gene ELL, which encodes a transcription elongation factor. The involved region of MLL was more 5′ than the secondary leukemia translocation breakpoint hotspot. The der (11) fusion transcripts joined MLL exon 7 to ELL exon 2, which is consistent with alternative splicing, and the der (19) fusion transcript joined ELL exon 1 to MLL exon 9. Conclusions: Secondary leukemias with MLL translocations have been associated with topoisomerase II poisons, but not with the agents administered to this patient. The entity that we describe is distinct from blast crisis, in which Ph’ positive subclones evolve to acquire additional alterations. This case establishes that persistent clonal abnormalities and/or dysplasia in Ph’ negative cells following imatinib therapy may not be benign and may herald AML transformation. With effective and selective molecular eradication of the Ph’ positive clone, the emergence of leukemia with independent abnormalities may become more common. This is a highly concerning clinical complication to consider with BCR-ABL targeted agents.
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