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Down syndrome (DS) is defined by an extra copy of chromosome 21 and confers an increased susceptibility to hematological disorders. Transient abnormal myelopoiesis (TAM) and myeloid‐leukemia associated with Down syndrome (ML‐DS) are two conditions that need to be accurately diagnosed to provide appropriate management. Both TAM and ML‐DS are characterized by proliferation of megakaryoblasts carrying a mutation in the GATA1 gene. Here, we report four cases with educational significance, highlighting typical diagnostic features that facilitate the differentiation between these two conditions, thereby assisting clinicians and medical laboratory professionals in effectively managing and monitoring these patients. [ABSTRACT FROM AUTHOR]

Background: Congenital malignancies are unusual fetal conditions, and therefore, the data on their prenatal manifestation are limited. Transient abnormal myelopoiesis (TAM) is a hematologic disorder characteristic for babies with trisomy 21 and based on the transient appearance of blast cells in peripheral blood. Methods: This paper presents prenatal manifestation of congenital TAM in a newborn with normal karyotype and reviews the literature on prenatal manifestation of this disorder. Results: A pregnant woman in her third pregnancy referred herself to the hospital for reduced fetal movements at 30 weeks of gestation. Admission's ultrasound scan showed an increased middle cerebral artery peak systolic velocity together with hepatomegaly. The patient was admitted to the labor ward for cardiotocography monitoring which showed acute fetal distress with repeated unprovoked decelerations. An emergency cesarean section was conducted and a phenotypically normal female newborn with low Apgar score was delivered. Further examination of the peripheral blood revealed anemia and leukocytosis with high blast proportion. A bone marrow aspirate revealed 70.2% of blasts in a sample with an abnormal karyotype of 47 XX+21. Cytogenetic analysis of the blasts with later microarray comparative genomic hybridization confirmed the presence of GATA1 mutation. However, the buccal smear showed a normal karyotype in the infant. The disease was classified as TAM. Conclusions: Our study demonstrates a rare case of prenatal manifestation of TAM in a neonate with a normal karyotype. Obstetricians should pay attention to symptoms like high MCA PSV and hepatosplenomegaly as possible causes of fetal hematological disorders and differentiate it with infection or isoimmunization. [ABSTRACT FROM AUTHOR]

BACKGROUND: Tumor lysis syndrome (TLS) is an oncological emergency associated with hematological malignancies or highly proliferative solid tumors, commonly after chemotherapy. It is rarely associated with transient abnormal myelopoiesis. OBSERVATION: We report a rare case of a neonate with transient abnormal myelopoiesis and tumor lysis syndrome, complicated with concomitant heart failure due to an underlying atrioventricular septal defect. Hyperhydration was contraindicated due to heart failure. The patient was managed conservatively with full recovery. CONCLUSION: Tumor lysis syndrome should be suspected in neonates with transient abnormal myelopoiesis with electrolyte abnormalities. Treatment options should be considered carefully for their risks and benefits. [ABSTRACT FROM AUTHOR]

Aim: Five to thirty percent of neonates with trisomy 21 develop transient abnormal myelopoiesis (TAM) with a high mortality rate. The aim of the study was to identify contributing factors that determine mortality and need for chemotherapy in this patient group. Methods: Six‐year, single‐centre, retrospective study of neonatal TAM cases requiring admission to intensive care. Data were collected from electronic patient records, laboratory and genetic results. The odds ratio was calculated to assess the likelihood of neonates with certain clinical characteristics having short‐term mortality and needing chemotherapy. Results: Twenty‐one neonates were studied with a mortality rate of 28%. Neonates requiring inotropic support (OR 19, 95% CI: 0.9–399, p = 0.05) and inhaled nitric oxide (iNO) (OR 13, 95% CI: 1.4–124.3, p = 0.03) were less likely to survive to discharge. Neonates needing mechanical ventilation (OR 14, 95% CI: 1.1–185.5, p = 0.04), or a white cell count >50 × 109/L (OR 27, 95% CI: 1.2–605.7, p = 0.04) were more likely to receive chemotherapy. Conclusion: A high mortality rate was identified in TAM neonates with symptomatic pulmonary hypertension (PH) needing active treatment strategies, such as inotropes and iNO. The presence of PH should be considered in the clinical management, prognosis and parental counselling. [ABSTRACT FROM AUTHOR]

Abstract Background Down syndrome myeloid hyperplasia includes transient abnormal myelopoiesis (TAM) and the myeloid leukemia associated with Down syndrome (ML-DS). The mutation of GATA1 gene is essential in the development of Down syndrome combined with TAM or ML-DS. Some patients with TAM are asymptomatic and may also present with severe manifestations such as hepatosplenomegaly and hydrops. Case presentation We report two cases of prenatally diagnosed TAM. One case was a rare placental low percentage 21 trisomy mosiacism, resulting in the occurrence of a false negative NIPT. The final diagnosis was made at 36 weeks of gestation when ultrasound revealed significant enlargement of the foetal liver and spleen and an enlarged heart; the foetus eventually died in utero. We detected a placenta with a low percentage (5–8%) of trisomy 21 mosiacism by Copy Number Variation Sequencing (CNV-seq) and Fluorescence in situ hybridization (FISH). In another case, foetal oedema was detected by ultrasound at 31 weeks of gestation. Two foetuses were diagnosed with Down syndrome by chromosomal microarray analysis via umbilical vein puncture and had significantly elevated cord blood leucocyte counts with large numbers of blasts. The GATA1 Sanger sequencing results suggested the presence of a [NM_002049.4(GATA1):c.220G > A (p. Val74Ile)] hemizygous variant and a [NM_002049.4(GATA1):c.49dupC(p. Gln17ProfsTer23)] hemizygous variant of the GATA1 gene in two cases. Conclusion It seems highly likely that these two identified mutations are the genetic cause of prenatal TAM in foetuses with Down syndrome.

Background: Down syndrome myeloid hyperplasia includes transient abnormal myelopoiesis (TAM) and the myeloid leukemia associated with Down syndrome (ML-DS). The mutation of GATA1 gene is essential in the development of Down syndrome combined with TAM or ML-DS. Some patients with TAM are asymptomatic and may also present with severe manifestations such as hepatosplenomegaly and hydrops. Case presentation: We report two cases of prenatally diagnosed TAM. One case was a rare placental low percentage 21 trisomy mosiacism, resulting in the occurrence of a false negative NIPT. The final diagnosis was made at 36 weeks of gestation when ultrasound revealed significant enlargement of the foetal liver and spleen and an enlarged heart; the foetus eventually died in utero. We detected a placenta with a low percentage (5–8%) of trisomy 21 mosiacism by Copy Number Variation Sequencing (CNV-seq) and Fluorescence in situ hybridization (FISH). In another case, foetal oedema was detected by ultrasound at 31 weeks of gestation. Two foetuses were diagnosed with Down syndrome by chromosomal microarray analysis via umbilical vein puncture and had significantly elevated cord blood leucocyte counts with large numbers of blasts. The GATA1 Sanger sequencing results suggested the presence of a [NM_002049.4(GATA1):c.220G > A (p. Val74Ile)] hemizygous variant and a [NM_002049.4(GATA1):c.49dupC(p. Gln17ProfsTer23)] hemizygous variant of the GATA1 gene in two cases. Conclusion: It seems highly likely that these two identified mutations are the genetic cause of prenatal TAM in foetuses with Down syndrome. [ABSTRACT FROM AUTHOR]

Trisomy 21 (Down Syndrome) may lead to multiple hematological and hepatobiliary manifestations including the development of transient abnormal myelopoiesis. While many cases resolve, transient abnormal myelopoiesis may lead to significant morbidity and mortality in a small percentage of patients. This condition may present a diagnostic challenge for physicians and currently there is only limited data on effective treatments, particularly with low blast percent transient abnormal myelopoiesis. We present a case of a neonate with trisomy 21 and multiple congenital anomalies who consequently developed hepatic failure with evidence of non-cirrhotic portal hypertension likely due to transient abnormal myelopoiesis. This clinical scenario highlights the need for additional evaluation for transient abnormal myelopoiesis associated hepatic disorder and possibly hepatic sinusoidal occlusive syndrome among trisomy 21 neonates particularly with low blast percentage. [ABSTRACT FROM AUTHOR]

Simple Summary: Patients with Down Syndrome have been thoroughly studied over the past 100 years, and many attempts have been made to attain insight into the developmental biology of DS. Given the association of DS with several hematological disorders, it was more than appealing to us to conduct a literature research to identify the rare subtype of acute myeloid leukemias associated with DS -Myeloid Leukemia of Down Syndrome- to investigate its occurrence, clinical presentation, and typical characteristics in terms of blast morphology and immunophenotype, and suggest optimal criteria for early diagnosis and progression monitoring. Among others, the multistep clonal evolution process is being analyzed here, while challenges on treatment of those patients are presented in detail. We suggested that a standardized holistic approach of care for children with Myeloid Leukemia of Down Syndrome should be ensured and applied to provide more enhanced outcomes to those patients. Myeloid leukemia of Down syndrome (ML-DS) is characterized by a distinct natural history and is classified by the World Health Organization (WHO) as an independent entity, occurring with unique clinical and molecular features. The presence of a long preleukemic, myelodysplastic phase, called transient abnormal myelopoiesis (TAM), precedes the initiation of ML-DS and is defined by unusual chromosomal findings. Individuals with constitutional trisomy 21 have a profound dosage imbalance in the hematopoiesis-governing genes located on chromosome 21 and thus are subject to impaired fetal as well as to neonatal erythro-megakaryopoiesis. Almost all neonates with DS develop quantitative and morphological hematological abnormalities, yet still only 5–10% of them present with one of the preleukemic or leukemic conditions of DS. The acquired mutations in the key hematopoietic transcription factor gene GATA1, found solely in cells trisomic for chromosome 21, are considered to be the essential step for the selective growth advantage of leukemic cells. While the majority of cases of TAM remain clinically 'silent' or undergo spontaneous remission, the remaining 20% to 30% of them progress into ML-DS until the age of 4 years. The hypersensitivity of ML-DS blasts to chemotherapeutic agents, including but not limited to cytarabine, and drugs' increased infectious and cardiac toxicity have necessitated the development of risk-adapted treatment protocols for children with ML-DS. Recent advances in cytogenetics and specific molecular mechanisms involved in the evolution of TAM and ML-DS are reviewed here, as well as their integration in the improvement of risk stratification and targeted management of ML-DS. [ABSTRACT FROM AUTHOR]

Transient abnormal myelopoiesis (TAM) is a unique disease occurring in Down syndrome (DS) infants from which most patients have spontaneous remission. This study aimed to evaluate the incidence and outcomes of TAM in a tertiary center in Thailand. We reviewed the records of 997 DS patients diagnosed between June 1993 and October 2019. From the 997 DS patients, 32 had been diagnosed with TAM. The incidence of TAM was 3.2% and an overall survival rate of 87.5%. A total of 2/28 who survived (7.1%) subsequently developed AML-DS at the ages of 2.1 and 4.5 years, respectively. The risk factors related with death included maternal multiparity, sepsis, skin bleeding, subcutaneous nodules, high WBC count, low hemoglobin, and elevated AST level. Abbreviations [ABSTRACT FROM AUTHOR]

Introduction: Transient abnormal myelopoiesis (TAM) is a transient, clonal myeloproliferative disorder unique to Down Syndrome (DS) babies. It is characterized by increased peripheral blasts and presence of GATA1 mutation. The clinical spectrum ranges from jaundice and hepatosplenomegaly to multi-organ failure and death. Here we present a case of a premature baby with DS diagnosed to have TAM with extramedullary involvement at birth who had a fatal outcome. Case report: A 30.3-week-old female fetus with DS had leukocytosis (WBC: 187.82 K/uL) with neutrophilia (ANC 27.65 K/uL), macrocytic anemia (RBC: 2.41 m/uL, Hb 8.8 g/dL, MCV 108.3, MCH 36.5, MCHC 33.7) and thrombocytosis (platelet count 361 K/uL) at birth. Liver panels demonstrated normal bilirubin levels with elevated liver enzymes (AST = 239 U/L, ALT = 216 U/L). Results: Peripheral smear showed marked leukocytosis with increased blasts (70%), nucleated RBCs, giant platelets, and megakaryocytic elements. Flow cytometry demonstrated two populations of cells: 20% myeloblasts and 26% dim CD45 CD34- cells. GATA1 mutation was present. Based on these findings a diagnosis of TAM with extramedullary hematopoiesis was made. She received two cycles of cytarabine chemotherapy. Though her WBC levels reached a low of 18.93 K/uL, she developed multi-organ failure, eventually leading to death on day 45. Discussion: TAM is a transient condition resulting in disease resolution in around 80% of cases. Death is reported in 10% of cases. Risk factors associated with early death include prematurity, hyperleukocytosis, elevated bilirubin levels. Management of high-risk babies with chemotherapy is recommended to improve survival.

Myeloid leukemia associated with Down syndrome (ML-DS) has a unique molecular landscape that differs from other subtypes of acute myeloid leukemia. ML-DS is often preceded by a myeloproliferative neoplastic condition called transient abnormal myelopoiesis (TAM) that disrupts megakaryocytic and erythroid differentiation. Over the last two decades, many genetic and epigenetic changes in TAM and ML-DS have been elucidated. These include overexpression of molecules and micro-RNAs located on chromosome 21, GATA1 mutations, and a range of other somatic mutations and chromosomal alterations. In this review, we summarize molecular changes reported in TAM and ML-DS and provide a comprehensive discussion of these findings. Recent advances in the development of CRISPR/Cas9-modified induced pluripotent stem cell-based disease models are also highlighted. However, despite significant progress in this area, we still do not fully understand the pathogenesis of ML-DS, and there are no targeted therapies. Initial diagnosis of ML-DS has a favorable prognosis, but refractory and relapsed disease can be difficult to treat; therapeutic options are limited in Down syndrome children by their stronger sensitivity to the toxic effects of chemotherapy. Because of the rarity of TAM and ML-DS, large-scale multicenter studies would be helpful to advance molecular characterization of these diseases at different stages of development and progression. [ABSTRACT FROM AUTHOR]

Simple Summary: Around 30% of children with Down Syndrome (DS) will develop Transient Abnormal Myelopoiesis (TAM) and 20% of them will progress to Acute Myeloid Leukemia (AML), mostly Megakaryoblastic Leukemia (AMKL). The optimal balance between treatment intensity and treatment-related toxicity has not yet been defined; neither the prognostic factors that determine the risk of developing AML nor the outcome. The aims of our retrospective study were to analyze the demographic/biological features of this population, identify possible risk factors and the optimal treatment. We observed that early intervention in TAM is effective to prevent a dismal outcome. The strongest poor-prognostic factor of DS-AML was sporadic DS-AML (non-AMKL immunophenotype), as well as complex karyotype and young age. Classical Myeloid Leukemia associated with DS (ML-DS) good outcome is mainly related to their low relapse rate. Even though the augmented sensitivity to chemotherapy seen in DS patients must be kept in mind, our data do not support the omission of high doses of cytarabine in ML-DS. Children with Down syndrome (DS) are at an increased risk of developing clonal myeloproliferative disorders. The balance between treatment intensity and treatment-related toxicity has not yet been defined. We analyzed this population to identify risk factors and optimal treatment. This single-center retrospective study included 78 DS patients <16 years-old with Transient Abnormal Myelopoiesis (TAM, n = 25), Acute Myeloblastic Leukemia (DS-AML, n = 41) of which 35 had classical Myeloid Leukemia associated with DS (ML-DS) with megakaryoblastic immunophenotype (AMKL) and 6 sporadic DS-AML (non-AMKL). Patients with DS-AML were treated according to four BFM-based protocols. Classical ML-DS vs. non-DS-AMKL were compared and the outcome of ML-DS was analyzed according to treatment intensity. Only four patients with TAM required cytoreduction with a 5-year Event-Free Survival probability (EFSp) of 74.4 (±9.1)%. DS-AML treatment-related deaths were due to infections, with a 5-year EFSp of 60.6 (±8.2)%. Megakaryoblastic immunophenotype was the strongest good-prognostic factor in univariate and multivariate analysis (p = 0.000). When compared ML-DS with non-DS-AMKL, a better outcome was associated with a lower relapse rate (p = 0.0002). Analysis of administered treatment was done on 32/33 ML-DS patients who achieved CR according to receiving or not high-dose ARA-C block (HDARA-C), and no difference in 5-year EFSp was observed (p = 0.172). TAM rarely required treatment and when severe manifestations occurred, early intervention was effective. DS-AML good outcome was associated with AMKL with a low relapse-rate. Even if treatment-related mortality is still high, our data do not support the omission of HDARA-C in ML-DS since we observed a trend to detect a higher relapse rate in the arm without HDARA-C. [ABSTRACT FROM AUTHOR]

Transient abnormal myelopoiesis (TAM), also known as transient myeloproliferative disorder or transient leukemia, is a self-regressing neoplasia that afflicts infants with trisomy 21. A recent review article documented "myeloid cell thrombus (MCT)" and "fetal vascular malperfusion (FVM)" in placentas with TAM, although the characteristic TAM placental findings have not been clarified. Here, we compared the clinical and pathological placental findings between trisomy 21 patients with or without TAM. In 13 cases of trisomy 21, we identified six placentas with TAM and seven placentas without TAM. The six placentas with TAM included two stillborn cases. Microscopically, MCT was noted in all the cases, and a high incidence of FVM (50%) was observed in TAM cases. Immunohistochemically, MCT was found to be a platelet-rich thrombus. The placentas were grouped according to the presence or absence of TAM and subsequently compared. Clinically, the incidences of abnormal fetal heart rate pattern and fetal or neonatal death were significantly higher in TAM cases. Pathologically, placenta in TAM cases weighted more than those in cases without TAM, and the incidence of MCT was significantly higher in placentas with TAM. Moreover, the incidence of FVM was higher in placentas with TAM, but this difference was not statistically significant. We propose that MCT is a diagnostic feature of placentas with TAM and may be associated with poor fetal outcomes. [ABSTRACT FROM AUTHOR]

Down syndrome (DS) is a congenital chromosomal abnormality caused by the presence of all or part of a third copy of chromosome 21 (+21). DS is frequently complicated by congenital heart or digestive tract diseases at birth. DS patients are prone to infections and have mental retardation, with dementia such as Alzheimer's disease showing in later life. Furthermore, malignancies with specific characteristics are also highly reported in DS patients compared with non-DS patients. Therefore, DS is believed to be a cancer predisposition syndrome due to the chromosomal instability. Acute myeloid leukemia (AML) and especially acute megakaryoblastic leukemia (AMKL) by French-American-British (FAB) classification are the most frequent hematological malignancies in DS patients, occurring at a rate that is 500 times higher than that in non-DS patients. Interestingly, transient abnormal myelopoiesis (TAM) is observed in approximately 10% of DS neonates with GATA1 mutations, and most TAM patients are asymptomatic and show spontaneous regression; however, about 10%–20% of TAM cases are fatal because of complications such as fetal effusion, liver fibrosis, and other complications.Acute lymphoblastic leukemia (ALL) is also associated with DS, occurring at a rate that is 20 times higher than that in non-DS patients. Furthermore, the prognosis of DS-ALL patients is poorer than that of non-DS-ALL patients. A recent genetic analysis revealed that more than half of DS-ALL cases have a mutation in the CRLF2–JAK pathway, indicating that JAK inhibitors might have a limited effect for DS-ALL patients.Notably, solid tumors such as neuroblastoma, Wilms tumor, and brain tumor, which are frequently observed in non-DS children, are rarely reported in DS children. The reason remains unknown, but it may be because of the triplication of the Down syndrome critical region 1 (DSCR1) gene on chromosome 21. In adult patients with DS, the expected age-adjusted incidence rates of solid tumors are low compared with age-matched euploid cohorts for most cancers except for testicular cancer. Although the average life expectancy of patients with DS will increase with advances in healthcare, the detailed health problems including cancer rates in older DS patients remain unknown. Therefore, these issues will be needed to be addressed in future studies.

Transient abnormal myelopoiesis (TAM) in neonates with Down syndrome is a distinct form of leukemia or preleukemia that mirrors the hematological features of acute megakaryoblastic leukemia. However, it typically resolves spontaneously in the early stages. TAM originates from fetal liver (FL) hematopoietic precursor cells and emerges due to somatic mutations in GATA1 in utero. In TAM, progenitor cells proliferate and differentiate into mature megakaryocytes and granulocytes. This process occurs both in vitro , aided by hematopoietic growth factors (HGFs) produced in the FL, and in vivo , particularly in specific anatomical sites like the FL and blood vessels. The FL's hematopoietic microenvironment plays a crucial role in TAM's pathogenesis and may contribute to its spontaneous regression. This review presents an overview of current knowledge regarding the unique features of TAM in relation to the FL hematopoietic microenvironment, focusing on the functions of HGFs and the pathological features of TAM. [Display omitted] • Transient abnormal myelopoiesis (TAM) in Down syndrome represents a unique self-regressing leukemia or preleukemia. • TAM emerges in the fetal liver (FL) by acquiring GATA1 mutations in the context of congenital trisomy 21. • TAM progenitor cells proliferate and differentiate into mature megakaryocytes and granulocytes. • This process occurs aided by hematopoietic growth factors produced in the FL. • The FL's microenvironment plays a crucial role in TAM's pathogenesis and may also contribute to its spontaneous remission. [ABSTRACT FROM AUTHOR]

Introduction: GATA1 mutation plays an important role in initiating transient abnormal myelopoiesis (TAM) and in the clonal evolution towards acute megakaryoblastic leukaemia (AMKL) associated with Down syndrome (DS). This study aimed to develop and validate the clinical utility of a complementary DNA (cDNA) analysis in parallel with the conventional genomic DNA (gDNA) Sanger sequencing (Ss), as an initial screening test for GATA1 mutations. Methods: GATA1 mutations were evaluated using both gDNA and cDNA in 14 DS patients using Ss and fragment analysis (FA), respectively. Results: The detection sensitivity of conventional gDNA sequencing was limited in low blast percentage TAM (LBP‐TAM); however, cDNA‐based Ss readily detected all the pathognomonic GATA1 mutations. The cDNA‐based FA readily detected GATA1 frameshift mutation with a reliable sensitivity ranging from 0.005% to 0.01% of clonal cells. Conclusions: GATA1 mutations are heterogeneous; therefore, we would like to propose a dual cDNA and gDNA analysis as a standard diagnostic approach, especially for LBP‐TAM. cDNA‐based FA promises an excellent sensitivity for detecting frameshift GATA1 mutations in the longitudinal clonal evolution towards AMKL without using a patient specific primer. [ABSTRACT FROM AUTHOR]

Simple Summary: Acute megakaryoblastic leukemia (AMKL) is a rare and heterogeneous subtype of acute myeloid leukemia (AML). We show that such patients can be identified by flowcytometric immunophenotyping using the standardized EuroFlow panel. AMKL patients show a unique immunophenotypic profile, and among AMKL patients, various subgroups can be distinguished. Acute megakaryoblastic leukemia (AMKL) is a rare and heterogeneous subtype of acute myeloid leukemia (AML). We evaluated the immunophenotypic profile of 72 AMKL and 114 non-AMKL AML patients using the EuroFlow AML panel. Univariate and multivariate/multidimensional analyses were performed to identify most relevant markers contributing to the diagnosis of AMKL. AMKL patients were subdivided into transient abnormal myelopoiesis (TAM), myeloid leukemia associated with Down syndrome (ML-DS), AML—not otherwise specified with megakaryocytic differentiation (NOS-AMKL), and AMKL—other patients (AML patients with other WHO classification but with flowcytometric features of megakaryocytic differentiation). Flowcytometric analysis showed good discrimination between AMKL and non-AMKL patients based on differential expression of, in particular, CD42a.CD61, CD41, CD42b, HLADR, CD15 and CD13. Combining CD42a.CD61 (positive) and CD13 (negative) resulted in a sensitivity of 71% and a specificity of 99%. Within AMKL patients, TAM and ML-DS patients showed higher frequencies of immature CD34+/CD117+ leukemic cells as compared to NOS-AMKL and AMKL-Other patients. In addition, ML-DS patients showed a significantly higher expression of CD33, CD11b, CD38 and CD7 as compared to the other three subgroups, allowing for good distinction of these patients. Overall, our data show that the EuroFlow AML panel allows for straightforward diagnosis of AMKL and that ML-DS is associated with a unique immunophenotypic profile. [ABSTRACT FROM AUTHOR]

Summary: Approximately 20% of patients with transient abnormal myelopoiesis (TAM) die due to hepatic or multiorgan failure. To identify potential new treatments for TAM, we performed in vitro drug sensitivity testing (DST) using the peripheral blood samples of eight patients with TAM. DST screened 41 agents for cytotoxic properties against TAM blasts. Compared with the reference samples of healthy subjects, TAM blasts were more sensitive to glucocorticoids, the mitogen‐activated protein kinase kinase (MAP2K) inhibitor trametinib, and cytarabine. Our present results support the therapeutic potential of glucocorticoids and the role of the RAS/MAP2K signalling pathway in TAM pathogenesis. [ABSTRACT FROM AUTHOR]

Children with Down syndrome (DS) are at increased risk of developing haematological malignancies, in particular acute megakaryoblastic leukaemia and acute lymphoblastic leukaemia. The microenvironment established by abnormal haematopoiesis driven by trisomy 21 is compounded by additional genetic and epigenetic changes that can drive leukaemogenesis in patients with DS. GATA-binding protein 1 ( GATA1 ) somatic mutations are implicated in the development of transient abnormal myelopoiesis and the progression to myeloid leukaemia of DS (ML-DS) and provide a model of the multi-step process of leukaemogenesis in DS. This review summarises key genetic drivers for the development of leukaemia in patients with DS, the biology and treatment of ML-DS and DS-associated acute lymphoblastic leukaemia, late effects of treatments for DS-leukaemias and the focus for future targeted therapy., Competing Interests: The authors declare that there is no conflict of interest., (© The Author(s), 2024.)

Children with Down syndrome (DS) are at an increased risk of developing transient abnormal myelopoiesis (TAM) and acute leukemia. Aberrant expression of CD56 has been observed on myeloid leukemic blasts in DS patients. In general, CD56 expression in acute myeloid leukemia (AML) is considered a promoter of leukemogenesis. We did a retrospective flow cytometric study to investigate mature myelomonocytic cell CD56 expression patterns in TAM, non-TAM, and leukemia cases with DS. Flow cytometric analysis showed that granulocyte and monocyte aberrant/dysplastic CD56 expression is an inherent characteristic of most DS patients irrespective of the presence of TAM or leukemia. Increased CD56 expression in monocyte and granulocyte populations in DS could be multifactorial; greater expression of RUNX1 secondary to the gene dose effect of trisomy 21 along with the maturational state of the cells are the potential contributors. Unlike AML seen in non-DS patients, CD56 overexpression in DS AML cases does not appear to play a role in leukemogenesis. [ABSTRACT FROM AUTHOR]

Abstract Pericardial effusion associated with transient abnormal myelopoiesis in Down's syndrome neonates needs to be diagnosed in a timely manner, and the comorbidities must be treated to prevent mortality. To our knowledge, the occurrence of basophilic/eosinophilic pericardial effusion without an increase of these cells in the peripheral blood and with no evidence of associated hypothyroidism is rare.

Transient abnormal myelopoiesis (TAM) is a unique clonal myeloproliferation characterized by immature megakaryoblasts that occurs in 5–10% of neonates with Down syndrome (DS). Although TAM regresses spontaneously in most patients, approximately 20% of TAM cases result in early death, and approximately 20% of survivors develop acute megakaryoblastic leukemia (AMKL). We retrospectively reviewed records of 35 DS patients with TAM to determine the correlation between clinical characteristics and blast percentage. Thirteen of the 35 patients were classified as low blast percentage TAM (LBP-TAM), defined as TAM with a peak peripheral blast percentage ≤ 10%. Although no patient with LBP-TAM experienced systemic edema, disseminated intravascular coagulation, or early death, eight patients had elevated direct bilirubin levels (> 2 mg/dl) and one developed AMKL. All patients with LBP-TAM had serum markers of liver fibrosis that exceeded the normal limits, and two patients underwent liver biopsy to clarify the etiology of pathological jaundice. Taken together, our results suggest that patients with LBP-TAM may be at risk of liver fibrosis and liver failure, similarly to patients with classical TAM. Although these patients generally have a good prognosis, they should be carefully monitored for potential development of liver disease and leukemia. [ABSTRACT FROM AUTHOR]

Clinical diagnosis of transient abnormal myelopoiesis (TAM) relies on the detection of characteristic blasts and leukocytosis in peripheral blood. We report two patients of trisomy 21 with TAM with hypereosinophilia, who had neither circulating blasts nor leukocytosis. Genetic testing of polymorphonuclear leukocytes isolated from whole blood revealed heterozygous mutations in GATA1, suggesting that the mutations were harbored in increased eosinophils. Both patients had direct hyperbilirubinemia and one died of liver fibrosis. Our findings emphasize the importance of screening for GATA1 mutations in neonatal infants with Down syndrome and hypereosinophilia even if blasts are not detected in peripheral blood smears. [ABSTRACT FROM AUTHOR]

Transient abnormal myelopoiesis (TAM) is a unique entity that usually occurs in children with Down syndrome (DS) or with trisomy 21 mosaicism. The somatic GATA1 mutation is a distinct feature of TAM. At presentation, TAM can resemble congenital leukemia (CL), which unlike TAM has an extremely poor prognosis and requires prompt therapeutic interventions. Therefore, correct and timely distinction between the two entities is crucial. We report a case of a phenotypically normal infant diagnosed with CL during the first weeks of life that retrospectively was reassessed as TAM. No acute myeloid leukemia (AML) specific mutations were found except for trisomy 21 confined exclusively to leukemic blasts. Retrospectively GATA1 mutation was also detected in malignant cells, but somatic genome appeared to be intact.

Background: Abnormal blood cell counts are characteristic of patients with Down syndrome and transient abnormal myelopoiesis (TAM). Although some patients with TAM experience prolonged anemia or thrombocytopenia, hematological factors predicting blood cell count recovery have not been reported yet. The aim of this study was to investigate the factors influencing platelet normalization in TAM. Methods: A retrospective review of the medical records of 21 patients with TAM admitted to the neonatal intensive care unit at Kanagawa Children's Medical Center between January 2007 and October 2014 was undertaken. Results: In the 16 of 21 patients (76%) experiencing transient thrombocytopenia, a large number of blasts at diagnosis was found to be significantly associated with late platelet recovery (R = 0.669, P < 0.05), and higher platelet counts at diagnosis were significantly associated with later recovery (R = 0.719, P < 0.01). Indeed, a strong positive correlation between blast and platelet counts at diagnosis was found (R = 0.730, P < 0.01). Conclusions: Our data suggest that high platelet counts at TAM diagnosis might reflect abnormal thrombocyte production from blasts. Thus, physicians should be aware of the possibility of prolonged thrombocytopenia in patients with TAM who exhibit a high platelet and/or blast count at diagnosis. [ABSTRACT FROM AUTHOR]

The article presents a case study of a 38 weeks of gestation male with facial dysmorphism and karyotype analysis revealing trisomy 21. Topics include mild thrombocytopenia and direct hyperbilirubinemia being noted but having neither increased peripheral blood blasts nor leukocytosis; and used for absolute quantification of nucleic acids based on the amplification of single molecules of a template with target-specific fluorescent-labeled assays.

Transient abnormal myelopoiesis (TAM) is a rare and unique disorder affecting Down syndrome (DS) newborns. This case series presents 5 cases of Down syndrome with TAM diagnosed during 2007–2015 with detailed analysis of immunophenotypic data of each case. CD34, CD13, CD33, CD117, CD41, CD61, CD7 and HLA-DR are useful markers for characterization of blasts of TAM.

Introduction: The incidence of myelodysplastic syndrome and acute myeloid leukemia is significantly increased in children with Down syndrome (DS). Within the revised 2016 WHO edition, these entities are jointly classified as myeloid leukemia associated with DS (ML-DS). Additionally, infants with DS may develop transient abnormal myelopoiesis (TAM) which is histomorphologically similar to ML-DS. While TAM is self-limiting, it is associated with an increased risk of subsequently developing ML-DS. Differentiating TAM and ML-DS is challenging but clinically critical., Methods: We performed a retrospective review of ML-DS and TAM cases collected from five large academic institutions in the USA. We assessed clinical, pathological, immunophenotypical, and molecular features to identify differentiating criteria., Results: Forty cases were identified: 28 ML-DS and 12 TAM. Several features were diagnostically distinct, including younger age in TAM (p &lt; 0.05), as well as presentation with clinically significant anemia and thrombocytopenia in ML-DS (p &lt; 0.001). Dyserythropoiesis was unique to ML-DS, as well as structural cytogenetic abnormalities aside from the constitutional trisomy 21. Immunophenotypic characteristics of TAM and ML-DS were indistinguishable, including the aberrant expression of CD7 and CD56 by the myeloid blasts., Discussion: The findings of the study confirm marked biological similarities between TAM and ML-DS. At the same time, several significant clinical, morphological, and genetic differences were observed between TAM and ML-DS. The clinical approach and the differential diagnosis between these entities are discussed in detail., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Pericardial effusion associated with transient abnormal myelopoiesis in Down's syndrome neonates needs to be diagnosed in a timely manner, and the comorbidities must be treated to prevent mortality. To our knowledge, the occurrence of basophilic/eosinophilic pericardial effusion without an increase of these cells in the peripheral blood and with no evidence of associated hypothyroidism is rare. [ABSTRACT FROM AUTHOR]

Neonates with Down syndrome (DS) have a propensity to develop the unique myeloproliferative disorder, transient abnormal myelopoiesis (TAM). TAM usually resolves spontaneously in ≤3 months, but approximately 10% of patients with TAM die from hepatic or multi‐organ failure. After remission, 20% of patients with TAM develop acute myeloid leukemia associated with Down syndrome (ML‐DS). Blasts in both TAM and ML‐DS have trisomy 21 and GATA binding protein 1 (GATA1) mutations. Recent studies have shown that infants with DS and no clinical signs of TAM or increases in peripheral blood blasts can have minor clones carrying GATA1 mutations, referred to as silent TAM. Low‐dose cytarabine can improve the outcomes of patients with TAM and high white blood cell count. A number of studies using fetal liver cells, mouse models, or induced pluripotent stem cells have elucidated the roles of trisomy 21 and GATA1 mutations in the development of TAM. Next‐generation sequencing of TAM and ML‐DS patient samples identified additional mutations in genes involved in epigenetic regulation. Xenograft models of TAM demonstrate the genetic heterogeneity of TAM blasts and mimic the process of clonal selection and expansion of TAM clones that leads to ML‐DS. DNA methylation analysis suggests that epigenetic dysregulation may be involved in the progression from TAM to ML‐DS. Unraveling the mechanisms underlying leukemogenesis and identification of factors that predict progression to leukemia could assist in development of strategies to prevent progression to ML‐DS. Investigation of TAM, a unique pre‐leukemic condition, will continue to strongly influence basic and clinical research into the development of hematological malignancies. [ABSTRACT FROM AUTHOR]

Infants with Down Syndrome (DS; trisomy 18) are under the risk for development of Transient Abnormal Myelopoiesis (TAM) during newborn period. TAM is mostly seen in classical form of DS but also might be seen in infants with mosaic type of DS. 4-10 % of infants with DS develop TAM. Most of infants with TAM, do not need any treatment and go into remission. Here, we tried to arouse interest on a newborn who has been consulted with compaints of vomiting and bloody stool and diagnosed as DownSyndrome with TAM. [ABSTRACT FROM AUTHOR]

A 38-year-old primiparous mother (gravida 1, para 0) at 27 weeks and 6 days' gestation reported that fetal movements had been absent for 6 days. All serological markers for infection were negative. Chorionic villus sampling at stillbirth delivery revealed trisomy 21 (47, XX, +21), indicative of Down syndrome. The macerated baby was female and weighed 1,290 g. There was no evidence of hydrops fetalis. Proliferating blast cells expressing megakaryoblastic/megakaryocytic antigen CD61 were mainly seen within the vessels, and some cells infiltrated outside of the vessels in almost all organs. Vessels of the umbilical cord and chorionic villi were filled with proliferating blast cells, but the blast cells were not apparent in the bone marrow. The diagnosis of transient abnormal myelopoiesis in Down syndrome was made. Hepatomegaly (64.5 g) was due to congestion and infiltration of CD61-positive blast cells within the vascular lumina and expanding outside the lumina accompanied by fibrotic change. The cause of death was attributed to liver insufficiency caused by liver fibrosis. An umbilical cord and chorionic villi examination may be helpful in the diagnosis of transient abnormal myelopoiesis when post-mortem examination is not permitted.

The article presents a guideline aimed at providing health care professionals with guidance on management of patients suffering from Transient Leukaemia of Down Syndrome(TL-DS). TL-DS may appear with overt clinical symptoms but some cases are only confirmed as a result of testing of the blood film or through GATA1 mutation evaluation.