Neonatal leukaemia.

Neonatal leukaemia is defined as occurring within the first 28 days of life and most, if not all, cases are congenital. With the exception of Down syndrome-associated transient abnormal myelopoiesis, which is not considered here, neonatal leukaemias are rare. In two-thirds of patients the disease manifests as an acute myeloid leukaemia, frequently with monocytic/monoblastic characteristics. Most other cases are acute lymphoblastic leukaemia, particularly B lineage, but some are mixed phenotype or blastic plasmacytoid dendritic cell neoplasms. The most frequently observed cytogenetic/molecular abnormality is t(4;11)(q21.3;q23.3)/KMT2A-AFF1 followed by t(1;22)(p13.3;q13.1)/RBM15-MKL1 and t(8;16)(p11.2;p13.3)/KAT6A-CREBBP. Common clinical features include prominent hepatosplenomegaly and a high incidence of skin involvement, sometimes in the absence of bone marrow disease. A distinctive feature is the occurrence of spontaneous remission in some cases, particularly in association with t(8;16). In this review, we summarise current knowledge of the clinical, cytogenetic and molecular features of neonatal leukaemia and discuss clinical management of these cases.

Clinicopathological features of transient myeloproliferative syndrome and congenital leukaemia.

OBJECTIVE: The objectives of the study were to determine the spectrum of the clinical and pathological findings, the management and prognosis of patients of transient myeloproliferative syndrome (TMS) and congenital leukaemia. STUDY DESIGN: Case series. PLACE AND DURATION OF STUDY: The study was conducted over a period of 8 years, from January 2000 to December 2007, at the Children's Hospital and the Institute of Child Health, Lahore. METHODOLOGY: Suspected patients presenting with fever, pallor, bruises and hepatosplenomegaly and diagnosed as either transient myeloproliferative disorder or congenital leukaemia were studied. The complete blood count, reticulocyte count, leukocyte alkaline phosphatase score, liver function tests, karyotyping studies and bone marrow aspiration biopsy were performed in all of those patients. Management and out come was noted. Results were described as frequency percentages. RESULTS: Out of 10,000 patients presenting during this period, 24 patients were diagnosed as either of transient myeloproliferative syndrome or congenital leukaemia. Fifteen of these were diagnosed as patients of TMS and 9 as patients of congenital leukaemia. Down syndrome (DS) was diagnosed in 75% of these patients. TMS patients were put on supportive treatment and recovered spontaneously. One DS patient with congenital leukaemia went into spontaneous remission and 2 of DS patients with congenital leukaemia responded to chemotherapy while rest of them either died or lost to follow-up. CONCLUSION: TMS and congenital leukaemia were not very uncommon in the studied population. Majority had Down syndrome. It is important to differentiate their clinical and pathological presentations for proper management. TMS may resolve with supportive treatment while congenital leukaemia is a fatal condition requiring chemotherapy.

A case of fetal leukemia with intracranial hemorrhage and early-onset jaundice. Fetal leukemia with intracranial hemorrhage and jaundice.

We report a case of a neonate who was diagnosed as having congenital leukemia after presenting with an intracranial hemorrhage. The chief symptom was early-onset jaundice due to the hemorrhage. The intracranial hemorrhage and post-hemorrhage hydrocephalus advanced. In addition, the leukemia worsened leading to death at 14 days old. The possibility of leukemia, although rare, should be considered as a cause of intracranial hemorrhage in term babies.

Fetal leukemia with umbilical artery embolism and circulatory failure.

BACKGROUND: This is a case report of fetal leukemia associated with hydramnios. CASE: When the hydramnios was treated with amnioreduction, near-term bradycardia was recorded ultrasonographically, resulting in immediate cesarean delivery. At birth, neonatal leukemia was diagnosed and there was no evidence of chromosomal abnormalities. The infant died of pulmonary hemorrhage. Autopsy showed umbilical venous embolization with tumor cells, and there was arterial invasion of the vessel wall by tumor. CONCLUSION: Fetal leukemia is extremely rare, and its prenatal diagnosis is difficult. In cases of hepatomegaly, fetal leukemia should be considered in the differential diagnosis.

Congenital leukemia cutis with subsequent development of leukemia.

We describe a newborn infant who was born with a purpuric rash and subcutaneous nodules. Skin biopsies demonstrated acute myeloid leukemia. Cytogenetic studies revealed an 11q23 rearrangement. Initial bone marrow and cerebrospinal fluid examination did not demonstrate medullary or meningeal disease. Chemotherapy was initiated on the basis of the abnormal cytogenetic findings in the skin biopsy. Intensive chemotherapy was, given but the infant's leukemia progressed. The patient died of refractory leukemia and secondary fungal disease. This case report supports the observation that leukemia cutis with an 11q23 rearrangement should be treated aggressively.

Natural transmission of gibbon leukemia virus.

Gibbon leukemia virus can infect prenatal gibbons through in utero infection or postnatal gibbons through contact transmission. The transmission of infectious virus was from viremic gibbons and not from uninfected or antibody-positive animals. The two modes of transmission could be distinguished by the amount of proviral DNA integrated into the muscle tissue of viremic gibbons. Muscle of gibbons infected postnatally had little or no proviral DNA, whereas gibbons infected prenatally had a large quantity of proviral DNA.

Rapid intraclonal switch of lineage dominance in congenital leukaemia with a MLL gene rearrangement.

We describe a case of neonatal mixed lineage leukaemia which presented with a dominant B progenitor lymphoblast population plus a minor monocytic component. Treatment of the patient with corticosteroid and Ara-C resulted in loss of lymphoblasts and a rapid (within 7 days) increase and dominance of the monocytic component. The common clonal origin of the two cell types was evident from the identical rearrangement in the MLL gene and a shared rearrangement of one IGH allele. In common with other neonatal or infant ALL with MLL gene rearrangements, this leukaemia may have originated in a common B-monocytic lineage stem cell during foetal haemopoiesis. The observations further suggest that the therapeutic impact of the MLL gene rearrangement is to some extent dependent on the cellular context in which it is expressed.

New structural chromosomal rearrangements in congenital leukemia.

The karyotypic abnormalities and clinical data on three patients in whom acute leukemia was diagnosed within the first 6 months of life are presented. The four structural chromosomal rearrangements detected in the bone marrow from these patients, i.e., t(7;12)(q36;p13) and t(1;19)(q11;q11) in case 1, t(2;10;11;12)(q21q31;p13;q13;q24) in case 2, and t(11;19)(q23;p13) in case 3, have not previously been associated with congenital leukemia. Acquired chromosomal changes have until now been reported in only 31 leukemic infants in this age group. Of the total material, 18 patients had acute lymphoblastic leukemia and 16 had acute nonlymphocytic leukemia. The by far most frequently recorded cytogenetic aberration has been t(4q;11q), seen in 14 cases of lymphoblastic leukemia. Although t(4q;11q) has not been found in a single patient with acute nonlymphocytic leukemia, these leukemias have often had other rearrangements involving the same region of 11q. Hence, genetic material around 4q21 may be active in lymphocytic differentiation, whereas gene(s) in 11q23 may be important in the neoplastic process in a less cell-type specific manner and perhaps particularly vulnerable to neoplastic rearrangement in fetal life. The finding of four cases out of 34 with translocations between 11q23 and chromosome 19 indicates that this rearrangement might characterize a specific cytogenetic subgroup of leukemia in the very young.

Hematological changes in Down's syndrome.

The many hematological abnormalities observed in patients with Down's syndrome have intrigued hematologists for many years. This review summarizes recent studies concerning the hematological findings in newborn infants with Down's syndrome, the transient leukemoid/leukemia-like proliferative disorders in these infants, the increased incidence of leukemia and types of leukemia in patients with Down's syndrome, and immunological studies of these patients. In addition, studies concerning the significance of the extra genetic material in chromosome 21 found in patients with Down's syndrome are discussed. It appears that the extra genetic material in chromosome 21 confers a proliferative advantage to hematopoietic stem cells, and may make them more prone to further karyotypic changes leading to leukemia. Megakaryocytic proliferative disorders are more common in patients with Down's syndrome. The spectrum of myeloproliferative disorders including myelofibrosis, myeloid metaplasia, and megakaryoblastic leukemia is seen in these patients. Studies of the genetic loci on chromosome 21 have demonstrated loci for enzymes involved in purine biosyntheses. Further studies of specific loci on chromosome 21 may help explain the hematopoietic growth advantages found in the stem cells with an extra chromosome 21.

11;19 translocation in a congenital leukemia with two cell populations of lymphoblasts and monoblasts.

This report describes a case of a female infant of congenital leukemia with a chromosomal translocation t(11;19) (q23;p13) which presented initially with lymphoid features and at relapse with monocytic ones. The clinical course and the results of sequential cytochemical, cytogenetic and immunological studies are considered to be consistent with the interpretation of leukemogenesis of the myelo-monocytoid progenitor cell which still retains the capability of exhibiting lymphoid features to a limited extent. Although leukemia with t(11;19) has been classified as ANLL, most commonly M5 of FAB classification, the patient with this chromosomal abnormality may have a mixed leukemia in which cells with lymphoid features and those with monocytic ones exist.

Transient leukemia with trisomy 21: description of a case and review of the literature.

Transient myeloproliferative disease (TMD) is often associated with a trisomy 21 cell line, but it is not always associated with clinical signs of Down syndrome. We report on a phenotypically normal newborn boy who presented with a high white blood cell count, undifferentiated blasts, and cutaneous leukemic infiltrates and compare this patient with the literature on TMD and trisomy 21. Chromosome analysis of bone marrow, and subsequently of skin fibroblasts, documented constitutional mosaicism for trisomy 21. A decrease in the frequency of blast cells paralleled a decrease in cells demonstrating trisomy 21 in hematopoietic tissues, and a complete clinical recovery was seen without the use of chemotherapy. Recognition of this transient form of congenital leukemia is important to prevent the unnecessary use of toxic chemotherapeutic agents in such patients.

Transient myeloproliferative disease of the newborn: case report with placental, cytogenetic, and flow cytometric findings.

Transient myeloproliferative disease (TMD) of the newborn is a rare hematologic abnormality associated with trisomy 21. It is frequently difficult to distinguish the disorder from true congenital leukemia (TCL). Unlike leukemia, which has a clinically aggressive course, TMD generally resolves within weeks to months. We present a case of TMD of the newborn diagnosed on the basis of peripheral blood studies and describe the pertinent pathological findings within the placenta. Flow cytometric analysis of the blasts in the peripheral blood showed phenotypic heterogeneity with features consistent with megakaryocytic differentiation. Cytogenetic studies showed trisomy 21 within the blastic cells. The placenta showed villous dysmaturity with associated chorangiosis and prominent intravascular aggregates of primitive-appearing cells with focal, early vascular wall invasion. The neonate recovered fully and shows no evidence of disease at 2 years of age.

Demographic study of leukaemia presenting within the first 3 months of life in the Northern Health Region of England.

AIMS: To determine the incidence and outcome of congenital leukaemia. METHODS: Retrospective population based study of putative leukaemia arising during the first 3 months of life over an 18 year period within the Northern Health Region of England. RESULTS: Nine infants with putative leukaemia were identified. Five had acute leukaemia and four had transient myeloproliferative disorder (TMD). Trisomy 21, either as Down's syndrome or perhaps restricted to proliferating marrow cells, was present in all four infants with TMD. The incidence of congenital acute leukaemia was 8.6/10(6) live births/year, but would be less than half this value if only patients presenting within 4 weeks of birth were counted. Remission was induced in three of the five patients with acute leukaemia. One patient, who presented at birth, remains well five years after diagnosis. All four patients with TMD survive. CONCLUSIONS: Congenital leukaemia is very rare but is not inevitably fatal. Finding trisomy 21 in spontaneously dividing blood or bone marrow cells of an infant with putative acute leukaemia, particularly within 3 months of birth, should encourage a cautious clinical approach and suggests that the diagnosis might be TMD.

Pentasomy 21 characterizing spontaneously regressing congenital acute leukemia.

Pentasomy 21 was found to characterize the proliferating cells in a case of transient congenital acute leukemia (or congenital acute leukemia) with spontaneous remission. The patient was phenotypically normal, and cytogenetically no evidence could be found for the existence of a mosaic with a normal cell line and one with more than two No 21 chromosomes. The importance of these findings is discussed.

Congenital acute nonlymphoblastic leukemia with translocation (9;18).

Chromosome analysis is becoming an increasingly important tool in the diagnosis and treatment of childhood malignancies. This report illustrates a new translocation t(9;18) in a neonate with congenital acute nonlymphocytic leukemia, which predicted a bone marrow relapse in a normal appearing bone marrow.

Congenital acute lymphoblastic leukemia with chromosomal abnormalities including a translocation (1;4;22).

Cytogenetic studies in a patient with inborn ALL demonstrated identical and complex abnormalities in all the cells, indicating a monoclonal origin. These abnormalities included, among others, a translocation (1;4;22).

Down's syndrome and leukemia: epidemiology, genetics, cytogenetics and mechanisms of leukemogenesis.

The association of Down's syndrome and leukemia has been documented for over 50 years. Multiple studies have established the incidence of leukemia in Down's syndrome patients to be 10- to 20-fold higher than that in the general population. The age of onset for leukemia in these children is bimodal, peaking first in the newborn period and again at 3-6 years. This increased risk extends into adulthood. All cytogenetic types of Down's syndrome apparently predispose to leukemia. The proportion of acute lymphoblastic leukemia and acute nonlymphoblastic leukemia in patients with Down's syndrome is similar to non-Down's syndrome leukemia patients matched for age. There are case reports in which leukemia, Down's syndrome, and other chromosomal aberrations cluster within a family. In these kindreds, there may be a familial tendency toward nondisjunction. Congenital leukemia also occurs with increased frequency in Down's syndrome patients, and is characterized by a preponderance of acute nonlymphoblastic leukemia (similar to non-Down's syndrome patients). Transient leukemoid reactions have been observed in Down's syndrome patients, as well as in phenotypically normal children with constitutional trisomy 21 mosaicism. The transient leukemoid reactions are characterized by a high spontaneous remission rate. However, in some Downs syndrome patients with apparent transient leukemoid reaction, leukemia relapse following periods of spontaneous remission have been reported. Cytogenetic studies of leukemic cells in Down's syndrome patients show a tendency toward hyperdiploidy. Besides trisomy 21, there is no other specific cytogenetic abnormality that is characteristic of the leukemia cells in Down's syndrome patients. The possible mechanisms for leukemogenesis in Down's syndrome patients may involve factors at the levels of the organism, the organ/system, the cell, the chromosomes or the DNA.

Transient abnormal myelopoiesis in Down's syndrome.

Recent data have elucidated the pathogenesis of transient abnormal myelopoiesis (TAM) to a great extent. TAM is a monoclonal disorder which resolves spontaneously and the target cell in this disorder is a multipotent stem cell which is capable of differentiating into megakaryocytes. The pathogeneses of TAM/AMKL (acute megakaryoblastic leukemia) appears to be closely associated with abnormal quality and quantity of a gene located on chromosome 21. AMKL developing after the regression of TAM appears to come from the same clone as the TAM, which apparently experiences some kind of genetic alterations. It seems that the gene responsible for TAM will soon be cloned in the near future. However, the mechanism of spontaneous regression of TAM has as yet not been clarified. The expanding clone in the transient physiological immunodeficient state, during the perinatal period, might be eliminated with the maturation of more mature immunosurveillance. Alternatively, the TAM clone might be destined to undergo spontaneous death, which is called "programmed cell death" (apoptosis). The mechanism of this phenomenon awaits further elucidation.