Congenital leukemia presenting as fever in a neonate.

BACKGROUND: Emergency department workup of pediatric fever typically focuses on ruling out serious bacterial infection, but other disease processes can cause fever. Congenital leukemia is a rare but important cause of fever in neonates. We review the presentation, pathophysiology, and potential complications of congenital leukemia presenting to the emergency department as pediatric fever. CASE REPORT: We report a case of a 4-week-old infant brought to the emergency department for fever and "not acting normally." Complete blood count demonstrated hyperleukocytosis. Subsequent bone marrow biopsy and flow cytometry confirmed the diagnosis of congenital leukemia. The extreme elevation of the patient's white blood cell count put her at high risk for complications, necessitating aggressive treatment, close monitoring, and appropriate consultation for comprehensive care. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS: Congenital leukemia is a rare but serious cause of neonatal fever. While the workup for fever without a source in young pediatric patients primarily focuses on ruling out serious bacterial illness, emergency physicians must be familiar with other potentially life-threatening causes of this complaint.

Excess congenital non-synonymous variation in leukemia-associated genes in MLL- infant leukemia: a Children's Oncology Group report.

Infant leukemia (IL) is a rare sporadic cancer with a grim prognosis. Although most cases are accompanied by MLL rearrangements and harbor very few somatic mutations, less is known about the genetics of the cases without MLL translocations. We performed the largest exome-sequencing study to date on matched non-cancer DNA from pairs of mothers and IL patients to characterize congenital variation that may contribute to early leukemogenesis. Using the COSMIC database to define acute leukemia-associated candidate genes, we find a significant enrichment of rare, potentially functional congenital variation in IL patients compared with randomly selected genes within the same patients and unaffected pediatric controls. IL acute myeloid leukemia (AML) patients had more overall variation than IL acute lymphocytic leukemia (ALL) patients, but less of that variation was inherited from mothers. Of our candidate genes, we found that MLL3 was a compound heterozygote in every infant who developed AML and 50% of infants who developed ALL. These data suggest a model by which known genetic mechanisms for leukemogenesis could be disrupted without an abundance of somatic mutation or chromosomal rearrangements. This model would be consistent with existing models for the establishment of leukemia clones in utero and the high rate of IL concordance in monozygotic twins.

Identification of somatic and germline mutations using whole exome sequencing of congenital acute lymphoblastic leukemia.

BACKGROUND: Acute lymphoblastic leukemia (ALL) diagnosed within the first month of life is classified as congenital ALL and has a significantly worse outcome than ALL diagnosed in older children. This suggests that congenital ALL is a biologically different disease, and thus may be caused by a distinct set of mutations. To understand the somatic and germline mutations contributing to congenital ALL, the protein-coding regions in the genome were captured and whole-exome sequencing was employed for the identification of single-nucleotide variants and small insertion and deletions in the germlines as well as the primary tumors of four patients with congenital ALL. METHODS: Exome sequencing was performed on Illumina GAIIx or HiSeq 2000 (Illumina, San Diego, California). Reads were aligned to the human reference genome and the Genome Analysis Toolkit was used for variant calling. An in-house developed Ensembl-based variant annotator was used to richly annotate each variant. RESULTS: There were 1-3 somatic, protein-damaging mutations per ALL, including a novel mutation in Sonic Hedgehog. Additionally, there were many germline mutations in genes known to be associated with cancer predisposition, as well as genes involved in DNA repair. CONCLUSION: This study is the first to comprehensively characterize the germline and somatic mutational profile of all protein-coding genes patients with congenital ALL. These findings identify potentially important therapeutic targets, as well as insight into possible cancer predisposition genes.

Phoma and Acremonium invasive fungal rhinosinusitis in congenital acute lymphocytic leukemia and literature review.

OBJECTIVE: Invasive rhinocerebral fungal infections are a difficult and often fatal problem in children with hematologic malignancies, with increasing reports of rare pathogens. We describe a case of congenital acute lymphoblastic leukemia (ALL) and invasive fungal rhinosinusitis involving Acremonium and Phoma species, not previously reported in invasive pediatric fungal rhinosinusitis, and review all published cases of human Phoma infections. METHODS: A literature and institutional review for Phoma spp. was completed including patient demographics, infection site, immune status, treatment and outcome. RESULTS: A female neonate with acute lymphoblastic leukemia presented with hyperleukocytosis and advanced invasive Phoma and Acremonium spp. rhinosinusitis. Despite aggressive medical and surgical therapy, the disease progressed to a rhinocerebral infection with a fatal outcome. Twenty cases of Phoma spp. were found in a complete literature search, including 6 females and 14 males from 18 months to 77 years old. Infections were superficial in fifteen patients and involved deeper tissue in five patients, with sites including cutaneous, subcutaneous and deep tissue sites (eye, lung, extremity deep tissue compartments). CONCLUSIONS: This case highlights the risks and grave prognosis of fulminant invasive fungal rhinosinusitis in the context of congenital leukemia, and the potential for rare fungal species in neonates with immunosuppression.

Congenital acute lymphoblastic leukemia: a two-case report and a review of the literature.

Congenital leukemia is a rare disease with particular biological and clinical characteristics which differs from those of older children and adults. Here, we describe two cases of congenital acute lymphoblastic leukemia in two newborns with different clinical presentations (leukemia cutis vs. splenomegaly and respiratory distress) and fatal outcome. Both cases shared the expression of myeloid antigens (CD65) and cytogenetic disorders involving the MLL gene (location 11q23) which are associated to extremely poor prognosis.

Vincristine-induced peripheral neuropathy in a neonate with congenital acute lymphoblastic leukemia.

We report the case of a 46-day-old boy with a fulminant vincristine-induced peripheral neuropathy after treatment for congenital acute lymphoblastic leukemia. Flaccid paralysis developed at the end of the first phase of induction, requiring intubation and ventilation for 51 days. Treatment was initiated with levocarnitine, N-acetylcysteine, and pyridoxine and progressive reversal of the neuropathy occurred over the next 4 months. Potential differences in pathogenesis and presentation of vincristine neurotoxicity and Guillian-Barre syndrome in the neonate are discussed.

Congenital MLL-positive B-cell acute lymphoblastic leukemia (B-ALL) switched lineage at relapse to acute myelocytic leukemia (AML) with persistent t(4;11) and t(1;6) translocations and JH gene rearrangement.

Congenital acute leukemia is a rare form of childhood leukemia, in which lineage conversion at relapse is very rarely reported. Here we describe a case of congenital B-cell acute lymphoblastic leukemia (B-ALL) with t(4;11) and t(1;6) translocations, which at relapse underwent a switch to monocytic lineage with persistence of the original cytogenetic translocations and clonal rearrangement of the JH gene. Similar to the other described cases of congenital acute leukemia with lineage conversion, our case had a MLL gene rearrangement and followed an aggressive clinical course.

Reactivation of the bacille Calmette-Guérin scar following immune reconstitution during treatment of infant acute lymphoblastic leukemia.

The authors describe an infant presenting at 2 weeks of age with congenital acute lymphoblastic leukemia who had previously received routine bacille Calmette-Guérin (BCG) vaccination at birth. The risk of BCG dissemination in immunocompromised infants is discussed and the use of antimycobacterial prophylaxis in such cases considered.

Treatment of leukemia relapse with recombinant granulocyte-macrophage colony stimulating factor (rhGM-CSF) following unrelated umbilical cord blood transplant: Induction of graft-vs.-leukemia.

An infant with congenital leukemia in complete remission (CR1) received an unrelated donor umbilical cord blood cell transplant from a one-HLA disparate donor. The conditioning regimen consisted of thiotepa, busulfan and cyclophosphamide. GVHD prophylaxis consisted of tacrolimus and mini-methotrexate. Engraftment occurred and a bone marrow aspirate obtained on day 28 showed 100% donor cells. The post-transplant course was complicated by skin and liver GVHD, grade III, that responded to therapy with methylprednisolone, anti-thymocyte globulin and daclizumab (Zenapax), in addition to tacrolimus. A bone marrow aspirate obtained on day 187 showed relapse, with 17% blasts. The patient was then treated for 30 days with recombinant human granulocyte-macrophage colony-stimulating factor treatment (rhGM-CSF). A bone marrow aspirate obtained 17 days after the initiation of rhGM-CSF treatment showed 2% blasts. Ascites was the predominant side-effect of the rhGM-CSF treatment. The patient remains in complete remission 24 months after relapse and 30 months after transplantation. This case documents that rhGM-CSF and withdrawal of immunosuppression can induce a durable complete remission after relapse following an unrelated donor cord blood transplant.

Differential chemosensitivity in a child with congenital relapsing acute lymphoblastic leukemia.

Described is a case of a boy with congenital acute lymphoblastic leukemia (ALL) with pre-pre-B-ALL immunophenotype, presenting as diarrhea, organomegaly, hyperleucocytosis of 1434 G/L, and tumor lysis syndrome. The lymphoblasts showed low proliferative activity and high in vitro drug sensitivity measured by the MTT assay. An excellent response to therapy was observed, but relapse ocurred 3 months later. On relapse, blasts showed extremely high drug resistance, high expression of P-glycoprotein, and high proliferative activity. The response to therapy was again positive, but a second relapse occurred in 1 month. The MTT assay indicated increasing drug resistance to all drugs. Cytogenetic analysis revealed deletion in 11q23 locus. This unfavorable case shows complex biology and differential drug resistance in congenital leukemia.

Congenital leukaemia: the Dutch experience and review of the literature.

We reviewed Dutch patients and those described in the literature with congenital leukaemia in the past 25 years, with the intention to obtain an overview of the characteristics of this rare disease. Among the 117 patients reviewed, acute myeloid leukaemia (AML) was more frequent (64%) than acute lymphoblastic leukaemia (ALL, 21%). Most patients had a high leukaemic cell load with hepatosplenomegaly, leukaemia cutis and hyperleucocytosis. Cytogenetic abnormalities were found in the majority of the patients tested (72%); 11q23 abnormalities were found in less than half of them (42%). The probability of overall survival at 24 months was only 23%. When congenital AML and ALL were compared, clinical characteristics and overall survival were not significantly different. However, in patients at risk, the probability of event-free survival (EFS) and disease-free survival (DFS) were significantly higher in AML than in ALL, 43% versus 13% and 68% versus 0% respectively. Among the congenital AML cases, six spontaneous remissions have been described. In conclusion, the clinical characteristics of congenital leukaemia differ from those of leukaemia in older children and prognosis is generally poor. Once complete remission is achieved, patients with AML fare better than those with ALL. Chemotherapy for congenital leukaemia needs improvement to increase the sustained remission rate.