Fetal hydrops and hepatosplenomegaly in the second half of pregnancy: a sign of myeloproliferative disorder in fetuses with trisomy 21

Smrcek, J.; Baschat, Ahmet; Germer, U.; Gloeckner-Hofmann, K.; Gembruch, Ulrich

doi:10.1046/j.1469-0705.2001.00384.x

Cited by 78 publications

(50 citation statements)

References 25 publications

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“…TMD results in abnormalities of one or more hematopoietic cell lines, and although its etiology is unclear, there is evidence that TMD represents a disorder of fetal liver hematopoiesis, with the process originating in utero. Fetuses have been diagnosed with TMD as early as 25 weeks gestation [Robertson et al, 2003], and there have been reports of prenatal diagnosis of fetal hydrops and hepatosplenomegaly in fetuses with DS [Smrcek et al, 2001]. The majority of patients present with TMD at birth or within the first few weeks of life and the time period of spontaneous remission correlates well with the timing of the switch from fetal liver to bone marrow hematopoiesis [Lange, 2000;Crispino, 2005a,b].…”

Section: Transient Myeloproliferative Disordermentioning

confidence: 98%

Clinical manifestations of hematologic and oncologic disorders in patients with Down syndrome

Dixon

Kishnani

Zimmerman

2006

American J of Med Genetics Pt C

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Hematologic abnormalities are common in individuals with Down syndrome (DS). Increased erythrocyte mean corpuscular volume (MCV) is frequently found among DS infants and remains elevated throughout life in two-thirds of patients, making interpretation of red cell indices for diagnosis of nutritional anemias or bone marrow failure disorders more challenging. Transient myeloproliferative disorder (TMD) associated with pancytopenia, hepatosplenomegaly, and circulating immature WBCs, is found almost exclusively in DS infants with an incidence of approximately 10%. In most cases, TMD regresses spontaneously within the first 3 months of life, but in some children, it can be life threatening or even fatal. Despite the high rate of spontaneous regression, TMD can be a preleukemic disorder in 20-30% of children with DS. The types of malignancy, response to therapy, and clinical outcome in children with DS are also unique. There is an increased risk of leukemia with an equal incidence of lymphoid and myeloid leukemia. Acute megakaryocytic leukemia (AMKL) subtype is the most common form of acute myeloid leukemia (AML) in this setting, and is uncommon in children without DS. Somatic mutations of the gene encoding the hematopoetic growth factor GATA1 have been shown to be specific for TMD and AMKL in children with DS. Myelodysplastic syndrome can precede AML. Children with DS and leukemia are more sensitive to some chemotherapeutic agents such as methotrexate than other children which requires careful monitoring for toxicity. Although the risk for leukemia is higher in individuals with DS, these patients have a lower risk of developing solid tumors, with the exception of germ cell tumors, and perhaps retinoblastoma and lymphoma.

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Section: Transient Myeloproliferative Disordermentioning

confidence: 98%

Clinical manifestations of hematologic and oncologic disorders in patients with Down syndrome

Dixon

Kishnani

Zimmerman

2006

American J of Med Genetics Pt C

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“…An ideal tissue in which to study mechanisms of mutagenesis in DS is the fetal liver for several reasons: (1) liver is the primary site for fetal hematopoiesis from the 6th to 22nd week of gestation (including the time period when we previously detected GATA1 mutations in fetal liver samples) 11 ; (2) fetal hydrops and hepatosplenomegaly (markers suggestive of TMD) were reported in 11 (14%) of 79 DS fetuses 34 ; and (3) hydrops could be detected by ultrasound in a 25-week gestation DS fetus and megakaryoblasts were found at autopsy. 35 To address this question further, gene expression was analyzed in fetal liver samples.…”

Section: Dna Repair In Dsmentioning

confidence: 99%

Mutational spectrum at GATA1 provides insights into mutagenesis and leukemogenesis in Down syndrome

Cabelof

Patel

Chen

et al. 2009

Blood

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Down syndrome (DS) children have a unique genetic susceptibility to develop leukemia, in particular, acute megakaryocytic leukemia (AMkL) associated with somatic GATA1 mutations. The study of this genetic susceptibility with the use of DS as a model of leukemogenesis has broad applicability to the understanding of leukemia in children overall. On the basis of the role of GATA1 mutations in DS AMkL, we analyzed the mutational spectrum of GATA1 mutations to begin elucidating possible mechanisms by which these sequence alterations arise. Mutational analysis revealed a predominance of small insertion/deletion, duplication, and base substitution mutations, including G:C>T:A, G:C>A:T, and A:T>G:C. This mutational spectrum points to potential oxidative stress and aberrant folate metabolism secondary to genes on chromosome 21 (eg, cystathionine-␤-synthase, superoxide dismutase) as potential causes of GATA1 mutations. Furthermore, DNA repair capacity evaluated in DS and non-DS patient samples provided evidence that the base excision repair pathway is compromised in DS tissues, suggesting that inability to repair DNA damage also may play a critical role in the unique susceptibility of DS children to develop leukemia. A model of leukemogenesis in DS is proposed in which mutagenesis is driven by cystathionine-␤-synthase overexpression and altered folate homeostasis that becomes fixed as the ability to repair DNA damage is com-

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“…TMD is reported to occur in 10%-20% of DS newborns. 6,7 It has a variable clinical presentation ranging from infants who have clinical abnormalities to infants who are well but have circulating blasts detected as an incidental finding. As blood counts and smears are not routinely performed on all DS newborns, it is possible that the reported incidence of TMD has been underestimated either because a blood count is not performed or because subtle abnormalities may be overlooked.…”

Section: Introductionmentioning

confidence: 99%

Natural history of GATA1 mutations in Down syndrome

Ahmed

Sternberg²,

Hall³

et al. 2004

Blood

226

201

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Fetal hydrops and hepatosplenomegaly in the second half of pregnancy: a sign of myeloproliferative disorder in fetuses with trisomy 21

Cited by 78 publications

References 25 publications

Clinical manifestations of hematologic and oncologic disorders in patients with Down syndrome

Clinical manifestations of hematologic and oncologic disorders in patients with Down syndrome

Mutational spectrum at GATA1 provides insights into mutagenesis and leukemogenesis in Down syndrome

Natural history of GATA1 mutations in Down syndrome

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