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Infant leukaemias

Congenital leukaemias

Neonatal leukaemias

Written1999-05Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France

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Identity

ICD-Topo C420,C421,C424 BLOOD, BONE MARROW, & HEMATOPOIETIC SYS
ICD-Morpho 9811/3 B lymphoblastic leukaemia/lymphoma, NOS
ICD-Morpho 9861/3 AML with mutated NPM1; AML with mutated CEBPA; Acute myeloid leukaemia, NOS
ICD-Morpho 9989/3 Myelodysplastic syndrome, unclassifiable
Atlas_Id 1084
Note
  • infant or congenital leukaemias are defined by a diagnosis within either the first month, the first year, or the first two years of life, according to different workers; recent data have shown that patients, diagnosed to have a leukaemia at age 5 mths and 2 yrs, already had a MLL-AF4 fusion gene in their neonatal blood spots/Guthrie cards
  • infant leukaemias have been suspected to have an environmental component:
    1- some of the leukaemias known to be often related to genotoxic exposure, such as the 11q23 leukaemias and the t(8;16) leukaemia, may also be found in infants;
    2- there has been a significant increase in infant acute leukaemias incidence of around 2.5% per year for 15 yrs, suggesting the presence of an environmental factor;
    3- infants with leukaemia (excluding Down syndrome cases) have more congenital anomalies (heart defects, digestive tract anomalies, mental delay)

  • they may be myelodysplasia or acute myeloid leukaemia (M4 or M5 mainly) in 1/2 to 2/3 of cases, or B-cell acute lymphocytic leukaemia (CD19+ or CD10+) in the remaining cases
  • sex ratio is balanced, both in AML and in ALL cases
  • frequent CNS involvement; WBC is often high, whatever the chromosome anomaly is; skin infiltrations (leukaemia cutis) may occur
  • 11q23 is found involved in 1/3 to 1/2 of cases (t(4;11), t(9;11), and t(11;19) representing nearly 1/10 of cases each)
    See also 11q23 rearrangements in childhood acute lymphoblastic leukemia: Clinical aspects
  • 4yr event free survival in infants ALL is 1/3 and median event free survival (EFS) is 1yr
  • in infants aged less than a month, 6 months survival is only 1/3, both in AML and in ALL
  • as the prognosis is most often very poor, bone marrow transplantation is indicated, apart in infant leukemia of the Down syndrome patient, were the prognosis is good
    		•

    Clinics and Pathology

    Disease Infant myelodysplasia
    Note they most often exhibit a normal karyotype or a monosomy 7
    Etiology exhibit a genetic background or is considered as idiopathic
    Epidemiology annual incidence : about 1 case per 106
    Prognosis has herein been calculated from 3 large studies (n= 47) : median survival was 31 mths; 6 yr survival was 43%

    Disease Down syndrome with M7
    Note Down syndrome patients have been known for long to be at increased risk (10 to 30 fold) of both ALL and AML; ALL is similar in Down syndrome (DS) and in the general population, whereas AML in DS is most often a specific entity of acute megakaryoblastic leukaemia (M7-AML); at least 20% of leukaemias in DS are M7, and other cases of M7-AML may also be misclassified as undifferentiated leukaemias or as ALL; therefore, the risk of M7 may well be 500 to 1000 times greater when the child has a DS; in other words, it may be that half of infants with M7 are DS ... and also that the risk of ALL in DS may not be as increased as previously claimed
    Epidemiology M7 leukaemia in Down syndrome infants annual incidence : 0.2 case per 106; median age at diagnosis is 22-23 mths
    Clinics there is often a preceeding myelodysplasia, or history of transient leukemoid reaction (a disease of the megakaryocytic lineage)
    Prognosis M7-AML has proved to be of better prognosis when in DS, with a recent study on 65 DS patients with M7, showing a 4 yr event free survival of 73%

    Disease 11q23 abnormalities
    Phenotype / cell stem origin M4 or M5 acute myeloid leukaemia (AML) or CD19+ B-cell acute lymphocytic leukaemia (ALL);
    Epidemiology 25% of 11q23 rearrangements cases are infant (<1 yr) cases; as much as 2/3 of cases of infant ALL leukaemias have been found in some studies to carry a 11q23 rearrangement, especially in infants < 6 mths old; a third to a half of infant AML cases also have a 11q23 rearrangement; however, 11q23 leukaemias can also be seen in children and in adults
    Clinics organomegaly; frequent CNS involvement; high WBC
    Prognosis median survival of 1yr, and a 3yr event free survival of 13% in a study and a 4 yr event free survival of 15% in another

  • t(4;11)(q21;q23) : CD19+ B-ALL; unbalanced sex ratio < 4 yrs (1M/2F); infants (<1 yr) accounting for 1/3 of t(4;11) cases; annual incidence could be 0.3-0.5 case per 106; prognosis: med EFS 7 mths; med survival 29mths; 3yr survival 40%; 3yr EFS: 30%; the gene involved in 4q21 is AF4

  • t(9;11)(p23;q23) : found in M5a or M4 AML; the rare ALL cases of t(9;11) are most often found in infants; infants cases (<1 yr) account for 15% of all t(9;11) cases; med EFS: 1yr, 3yr EFS 20%; the gene involved in 9p22 is AF9

  • t(10;11)(p12;q23) : rare; M4 or M5 AML; ALL at times; infants represent 40% of cases; the gene involved in 10p12 is AF10

  • t(11;19)(q23;p13.3): ALL, biphenotypic AL and M4 or M5 AML; half cases of t(11;19)(q23;p13.3) are infant cases; a study on 40 cases showed that med survival was 5 mths, with a 2yr survival of 20% (unpublished observation); the gene involved in 19p13.3 is ENL

  • other 11q23 rearrangements are rarely found in infants leukaemias

  • in 11q23 sits MLL, which encodes a 431 kDa protein; contains two DNA binding motifs (a AT hook, and Zinc fingers), a DNA methyl transferase motif, a bromodomain; transcriptional regulatory factor; nuclear localisation; wide expression; homology with trithorax (drosophila); the fusion protein includes the N-term AT hook and DNA methyltransferase from MLL fused to (little or most of) the partner C-term part from the other chromosome

    • Disease t(1;22)(p13;q13)
    Phenotype / cell stem origin M7 AML
    Epidemiology 39 cases so far described; <0.1 case per 106 (perhaps much less); the only leukaemia (nearly) restricted to infant cases; median age is 4 mths
    Clinics organomegaly, bone marrow fibrosis; misdiagnosis of a solid tumour is frequent
    Prognosis remission is obtained in only half cases, median survival is 7 mths

    Disease 12p abnormalities
    Phenotype / cell stem origin B lineage ALL mainly (CD10+); M5 AML at times
    Epidemiology at least 9 cases
    Prognosis no sufficient data

    Disease inv(16)(p13q22)
    Phenotype / cell stem origin M4 AML
    Epidemiology at least 3 cases reported
    Clinics high WBC, CNS involvement
    Prognosis is very poor so far (remission duration : 0, 2, 6 mths), in contrast with the usual inv(16) prognosis

    Disease t(5;15)(p15;q11)
    Phenotype / cell stem origin B lineage ALL
    Epidemiology 5 known cases
    Prognosis unknown; CR in 5/5

    Disease t(8;16)(p11;p13)
    Phenotype / cell stem origin M5/M4 AML
    Epidemiology at least 3 cases
    Prognosis survival : 0.5 mth, 22 mths+, 24 mths+

    Disease +19 and/or +21
    Phenotype / cell stem origin AML and ALL
    Epidemiology at least 5 cases
    Prognosis no survival data available

    Disease other chromosome rearrangements : +8 (solely or not), found in a few cases, del(6q), , and non recurring anomalies, found in at least one case each; finally, the kayotype has been found to be normal in a percentage of cases

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    Citation

    This paper should be referenced as such :
    Huret, JL
    Infant leukaemias - Congenital leukaemias - Neonatal leukaemias
    Atlas Genet Cytogenet Oncol Haematol. 1999;3(2):89-92.
    Free journal version : [ pdf ]   [ DOI ]
    On line version : http://AtlasGeneticsOncology.org/Anomalies/InfantLeukID1084.html

    Other genes implicated (Data extracted from papers in the Atlas) [ 2 ]

    Genes BEX2 KMT2A

    External links

    COSMICHisto = - Site = haematopoietic_and_lymphoid_tissue (COSMIC)
    arrayMap (UZH-SIB Zurich)Topo ( C42) Morph ( 9811/3) -   [auto + random 100 samples .. if exist ]   [tabulated segments]
    arrayMap (UZH-SIB Zurich)Topo ( C42) Morph ( 9861/3) -   [auto + random 100 samples .. if exist ]   [tabulated segments]
    arrayMap (UZH-SIB Zurich)Topo ( C42) Morph ( 9989/3) -   [auto + random 100 samples .. if exist ]   [tabulated segments]
     
     
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