Leukemoid Reaction and Preterm Birth: A Case Report of FIRS (Fetal Inflammatory Response Syndrome)

This article describes a case of severe hyperleukocytosis in a preterm infant with fetal inflammatory response syndrome (FIRS) associated with funisitis of umbilical cord and intrauterine inflammation. FIRS is a cause of leukocytosis in newborn, as well as leukemoid reaction in 21 trisomy, congenital leukemia, sepsis, and steroid prophylaxis. Inflammatory response syndrome is associated with high mortality, developmental impairment and complications of prematurity like intraventricular hemorrhage, chronic lung disease, periventricular leukomalacia, and sepsis.

Parvovirus Infection and Congenital Leukemia: Is It a Causal or Casual?

Congenital leukemia is an extremely rare disease but frequently fatal. We report a case of intrauterine death (IUD) secondary to congenital erythroid leukaemia associated with maternal Parvovirus B19 infection. Further research is needed to ascertain the association between maternal Parvovirus B19 infection and congenital leukemia.

Genomic Analysis of Congenital Myeloid Sarcoma Identifies Significant Bone Marrow Involvement in the Absence of Morphologic Blasts

Myeloid sarcoma is a tumor mass consisting of blasts at extramedullary sites, most frequently the skin and soft tissues. Skin involvement, also termed leukemia cutis, is a well-described entity in congenital leukemia and is present in approximately 50% of patients diagnosed within the first 4 weeks of life. Most cases of congenital leukemia cutis harbor KMT2A rearrangements, as do up to 80% of cases of infantile leukemia, and are typically accompanied by bone marrow involvement. Here we describe a rare CIC-rearrangement as the driver mutation for a case of congenital cutaneous myeloid sarcoma in a newborn female who was noted at birth to have a violaceous, nodular rash. Skin biopsy of the nodular rash shortly after birth with immunohistochemical staining was consistent with myeloid sarcoma. Bilateral bone marrow aspirates and biopsies were also performed, but failed to reveal an aberrant blast population by morphology and flow cytometry. Cytogenetics of the cutaneous myeloid sarcoma was significant for t(10;19)(q23;q13.2) and fluorescence in situ hybridization performed on the tumor confirmed a CIC-rearrangement. CIC-rearranged sarcomas are a new entity of undifferentiated small round cell sarcoma characterized by fusion events involving the CIC gene but are not a known to be driver mutations in myeloid neoplasms. Despite the absence of a blast population in the bone marrow, 75% of analyzed metaphases carried the t(10;19)(q23;q13.2). To further explore the underlying genomic events, whole genome, exome, and transcriptome sequencing was performed on both sarcoma and bone marrow specimens. Sequencing revealed an in-frame CIC-NUTM2A fusion gene present in both the skin and the bone marrow which has been previously described in a single case of undifferentiated soft tissue sarcoma. There were no large-scale chromosomal losses or gains and no copy neutral loss of heterozygosity events. Two exonic single nucleotide variations (SNVs) were detected, both of which were limited to the skin sarcoma and not predicted to be pathogenic. In vitro and in vivo modeling demonstrated that the CIC-NUTM2A fusion protein was highly leukemogenic. Colony forming assays performed using transduced murine bone marrow revealed that the CIC-NUTM2A fusion conferred self-renewal in contrast to CIC, NUTM2A, and the reciprocal NUTM2A-CIC product which failed to serially replate (p<0.001). Transplantation of CIC-NUTM2A modified murine bone marrow cells resulted in a fully penetrant myeloid leukemia with a median survival of 21 days in primary transplants and 16 days in secondary transplants. Transcriptome analysis of these tumors revealed a distinct gene expression profile when compared to several classic myeloid associated fusion genes including AML1-ETO and MLL-AF6. To further understand the acquisition of a malignant phenotype by morphology between the bone marrow and the sarcoma, targeted deep sequencing was performed for all tier 1, 2 and 3 mutations identified by whole genome and exome sequencing. A shared ancestral clone was identified in both specimens along with three subclones specific to the sarcoma. Four SNVs acquired in the sarcoma were found to be present in regulatory regions of genes that were also differentially expressed between the sarcoma and the bone marrow including C6orf120, SMURF1, TJAP1, and PID1. PID1 was found to be downregulated in the malignant sarcoma specimen and has been previously shown to be a regulator of the AKT/PI3K pathway. Low PID1 expression has been associated with poor outcomes in other malignancies, including pediatric glioblastoma. A genome wide CRISPR screen of our CIC-NUTM2A positive murine leukemia cells revealed an enrichment for PID1 deficient cells as well as PTEN confirming the cooperativity between CIC-NUTM2A and the AKT/PI3K pathway (p=0.009 and p=0.005 respectively). In conclusion, we describe a rare fusion gene, CIC-NUTM2A, which leads to an aggressive myeloid malignancy in both humans and mice. Targeted deep sequencing demonstrated the clonal evolution from the bone marrow and acquisition of a cooperating mutation targeting the AKT/PI3K pathway in a subset of extramedullary cells that led to morphologic transformation. A thorough interrogation of the bone marrow in patients with myeloid sarcoma is warranted even in the absence of morphologic and immunophenotypic blasts by flow cytometry to optimally track residual disease during treatment. Disclosures No relevant conflicts of interest to declare.

Analysis of 59 cases of congenital leukemia reported between 2001 and 2016

Congenital leukemia (CL), defined as manifestations of leukemia within the first 4 weeks of life, is a rare condition with an estimated incidence of only 1 to 5 per million live births. Despite extensive research and the clinical application of new therapies, the prognosis of CL remains poor. Few large-scale studies have investigated the factors affecting the outcomes of infants with CL. Here, we conducted a retrospective study and analysis of CL cases published in the English language from 1 January 2001 to 1 May 2016. Our goal was to provide updated information about this rare disease and to investigate factors that may affect the outcomes of patients with CL.

Congenital Leukemia Report of 2 Cases

Two cases of congenital leukemia are reported, one of which was associated with Down's syndrome. Both cases were lymphoblastic as observed morphologically and by the negative Sudanophilia. To the best knowledge of the authors these cases are the first two cases of congenital leukemia reported in the Indonesian medical literature.

Acute lymphoblastic congenital leukemia as a cause of perinatal death following massive cerebral hemorrhage

Background Congenital leukemia is a rare condition and most commonly found in infants with Down syndrome. The occurrence in newborns without a genetically predisposing syndrome is extremely infrequent. Highlights We describe a case of peripartal fetal death at 30 weeks and 4 days of gestation. Emergency cesarean section was performed after a previously uncomplicated pregnancy because of pathologic fetal heart rate tracing and suspected intracranial hemorrhage on ultrasound imaging. Resuscitation of the newborn was unsuccessful and stopped after 30 min, when ultrasound of the fetus confirmed very severe intracranial and intraabdominal bleeding. Autopsy was performed after informed consent and demonstrated evidence of acute lymphoblastic leukemia in the bone marrow, associated with wide spread visceral involvement. Conclusion Perinatal fetal demise due to congenital leukemia is exceedingly rare and can occur unexpectedly in the third term after a normal pregnancy. We here report the clinical and pathologic findings, discuss the pathogenesis of fetal leukemia and its clinical manifestations along with a thorough review of the relevant literature.