Cases Of Transient Abnormal Myelopoiesis Research Articles

Post-transplant transient abnormal myelopoiesis evolving from a GATA1 mutant clone in umbilical cord blood.

Transient abnormal myelopoiesis (TAM) generally affects newborns with Down syndrome and is associated with constitutional trisomy 21 and a somatic GATA1 mutation. Here we describe a case of TAM which evolved after umbilical cord blood transplantation (UCBT), whose origin was identified as a GATA1 mutation-harboring clone in umbilical cord blood (UCB) by detailed genetic analyses. A 58-year-old male who received UCBT for peripheral T-cell lymphoma presented progressive anemia and thrombocytopenia, and leukocytosis with blast cells in the peripheral blood (PB). Bone marrow (BM) aspiration showed granulocytic and megakaryocytic dysplasia with excess blasts whose karyotype was trisomy 21. Short tandem repeat analysis showed complete donor chimerism. He was initially diagnosed as donor-derived myelodysplastic syndrome (MDS) and treated with azacitidine, followed by secondary transplantation using unrelated BM, providing durable complete remission. Retrospective targeted-capture sequencing analysis of PB/BM samples collected at multiple timepoints identified trisomy 21 and a GATA1 mutation, suggestive of a diagnosis of donor cell-derived TAM (DC-TAM). Importantly, a minor clone with the same GATA1 mutation was detected in UCB by droplet digital PCR. DC-TAM is a rare UCBT-related complication which resembles MDS, but the identification of GATA1 mutation may be useful for its diagnosis. Our genetic analyses revealed that a pre-existing clone in UCB may contribute to the development of donor cell-derived hematologic neoplasms, highlighting the potential relevance of genetic screening of donor UCB.

Transient abnormal myelopoiesis requiring advanced neonatal intensive care treatment.

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. 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. 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. 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.

Myeloid Leukemia of Down Syndrome.

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.

Myeloid Proliferations Associated with Down Syndrome: Clinicopathologic Characteristics of Forty Cases from Five Large Academic Institutions

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 < 0.05), as well as presentation with clinically significant anemia and thrombocytopenia in ML-DS (p < 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.

Myeloid cell thrombus and fetal vascular malperfusion in placentas with transient abnormal myelopoiesis.

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.

Cytokine Analysis in 154 Patients with Transient Abnormal Myelopoiesis: Jccg JPLSG TAM-10 Clinical Study

Introduction:Transient abnormal myelopoiesis (TAM), also known as transient leukemia or transient myeloproliferative disorder, is a unique clonal myeloproliferation characterized by immature megakaryoblasts occurring in 10% of neonates with Down syndrome. Although most patients show spontaneously resolution of TAM without therapeutic interventions, approximately 20% of TAM cases result in early deaths, i.e., within 9 months, and approximately 20% of the survivors develop acute megakaryoblastic leukemia (AMKL) within 4 years. A somatic GATA1 gene mutation that leads to the exclusive expression of a truncated GATA1 protein is shared by both TAM and AMKL cells. According to previous reports, cytokine levels are associated with liver failure, which is a cause of early death. Here, we analyzed 154 DS patients with TAM enrolled in the TAM-10 prospective observational study conducted by the Japan Pediatric Leukemia/Lymphoma Study Group to determine the association between clinical characteristics and cytokine levels in such patients.Patients and Methods:A total of 167 neonates (89 boys and 78 girls) diagnosed with TAM were prospectively registered in the TAM-10 study between May 2011 and February 2014. We analyzed cytokine levels in 154 of the 167 enrolled patients whose samples were available. Somatic GATA1 gene mutations were confirmed in 151 (98%) of 154 patients using Sanger and/or next-generation sequencing. Using the Bio-Prex cytokine assay, serum concentrations of the following 27 cytokines were measured: interferon gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), vascular endothelial growth factor (VEGF), platelet-derived growth factor-BB (PDGF-BB), basic fibroblast growth factor (bFGF), granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory proteins alpha and beta (MIP-1α and MIP-1β), eotaxin, interferon gamma-induced protein (IP-10), regulated upon activation, normal T-cell expressed and secreted, interleukin I receptor agonist (IL-RA), and 13 different interleukins (IL-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12, IL-13, IL-15, and IL-17). For all analyses, P values were two-tailed and a P value of <0.05 was considered statistically significant. Mann-Whitney test were used as appropriate for comparisons between groups. Moreover, the cumulative incidence for competing events was compared with the Gray test.Results:The median (range) white blood cell (WBC) count at diagnosis was 37.2 (2.4-478.7) × 10 9 cells/L. Forty-seven (31%) of 154 patients received low-dose cytarabine. When we compared 29 patients with a high WBC count (≥100 × 10 9 cells/L, known as a poor prognostic factor in TAM patients) to 125 patients without a high WBC count for 27 cytokine levels, the levels of 16 cytokines (IL-1b, IL-1ra, IL-6, IL-7, IL-8, IL-9, IL-10, IL-13, Eotaxin, PDGF-bb, basic FGF, G-CSF, GM-CSF, MCP-1b, and VEGF) were significantly higher in patients with a high WBC group. Early death occurred in 14 (9%) of 154 patients. Cytokine levels were compared between the early death group (n = 14) and remaining patients (n = 140) and it was observed that the levels of 10 cytokines (IL-1b [p = 0.016], IL-1ra [p < 0.001], IL-6 [p < 0.001], IL-7 [p = 0.009], IL-8 [p < 0.001], IL-10 [p = 0.014], IL-13 [p = 0.002], MCP-1 [p = 0.030], MIP-1b [p = 0.024], and TNF-α [p = 0.008]) were significantly higher in the early death group. When the patients were divided in two groups according to the median IL-1β concentration showing the lowest p-value, the early death rate in the IL-1β high group was significantly higher than that in the IL-1β low group (16% vs. 3%, p < 0.001). IL-1, IL-6, IL-8, and TNF-α are proinflammatory cytokines induced by MCP-1 and MIP1-b. Early death was strongly associated with hypercytokinemia, suggesting that therapeutic interventions (e.g., systemic steroid therapy) may be effective in patients with hypercytokinemia. However, there was no relation between the levels of 27 cytokines and leukemia development.Conclusion:Our findings suggested that measurement of cytokine levels may be a useful marker for predicting early death and an indicator of therapeutic interventions required in TAM patients. DisclosuresNo relevant conflicts of interest to declare.

Mature Analysis of the Prospective Oxford Down Syndrome (DS) Cohort Study: Timing and Clinical Impact of Preleukemic GATA1 Mutations and Lessons for Management of Newborns with DS

Children with Down syndrome (DS) have a high risk of developing a unique form of AML known as myeloid leukaemia of DS (ML-DS) defined by the presence of one or more acquired N-terminal truncating mutations in the hematopoietic transcription factor gene GATA1 . ML-DS is confined to children <4 y of age and preceded by a neonatal preleukemic syndrome, Transient Abnormal Myelopoiesis (TAM). Although the same GATA1 mutations are present in ML-DS and TAM, indicating they are clonally-linked disorders, chemotherapy is essential to cure ML-DS whereas most cases of TAM spontaneously resolve without treatment.To determine the natural history of GATA1 mutations in DS and the true risk of subsequent leukemia conferred by GATA1 mutations we established the Oxford DS Cohort Study that prospectively analyses serial clinical, hematological and GATA1 mutational data from children with DS from birth to age 4y. All children had serial blood counts and smears and mutation analysis of exon 2/3 of GATA1 by next-generation-sequencing (NGS). A diagnosis of TAM was made if peripheral blood (PB) blasts were >10% and a GATA1 mutation was detected. DS neonates with PB blasts <10% and a GATA1 mutation were designated Silent TAM as our previous data on 18/80 DS neonates with blasts <10% showed that small mutant GATA1 clones were clinically and hematologically undetectable [Roberts et al, Blood 2013].We have now studied 471 neonates (gestational age [GA] at birth 29-42 wks) with karyotypically-confirmed DS. 130/471 (27.6%) had >1 GATA1 mutation confirming the high frequency of GATA1 mutations in DS neonates. Multiple GATA1 clones (2-7) were detected in 19% of TAM and 21% of Silent TAM (p=ns). A diagnosis of TAM was made in 55/471 (11.7%). 75/471 (15.9%) had Silent TAM and 341/471 had no GATA1 mutations. Typical clinical findings of TAM (hepatomegaly, splenomegaly, skin rash and effusions) were uncommon in Silent TAM, affecting 7%, 1.3%, 1.3% and 3% neonates respectively compared to 40%, 29%, 17% and 10% of neonates with TAM (p<0.0001). There were no specific hematological abnormalities in Silent TAM: median WBC and blasts were not increased: 13.1x109/L v 14.5x109/L and 4% v 4% (Silent TAM v no GATA1 mutation) and no neonates with Silent TAM had leucocytosis (WBC >35x109/L) or anemia. There was a strong correlation (r=0.753; p<0.0001) between PB blast% and mutant GATA1 clone size (assessed by VAF) with a greater mutant clone size in TAM v Silent TAM (median VAF 17.1% v 1.2%; p<0.0001).Unexpectedly, clone size was inversely proportional to GA (r=-0.2569; p=0.004). Despite similar median GA at delivery for all 3 groups, no GATA1 mutations were detected before 31 wks GA and no cases of TAM before 33 wks; the highest frequency of GATA1 mutations was seen at 34-35 wks GA (40%) reducing to 7% at >40 wks. This suggests GATA1 mutations are likely to be acquired and expand during a narrow time window early in the 3rd trimester of fetal life. Consistent with this, GATA1 mutations were not detected in 16 DS fetal liver samples (GA 8-19 wks) analysed over the same period. Similarly, in a case of TAM presenting in utero with fetal pericardial effusion and 96% PB blasts at 27 wks GA, the blast% and mutant GATA1 VAF spontaneously fell progressively (blasts 19%; VAF 23% at birth at 34 wks GA; undetectable at 4 wks postnatal age).Outcome: 7 neonates developed ML-DS: 6/52 survivors with TAM; 1/71 survivors with Silent TAM and 0/328 survivors without neonatal GATA1 mutations; 2/451 survivors developed ALL (1 Silent TAM, 1 no GATA1 mutation). 5 yr overall survival was the same in all 3 groups (95.1%, 95.8%, 95.1% for TAM, Silent TAM and no GATA1 mutations; Plog-rank 0.8994) while 5 yr event-free survival was lower in TAM (89.2%, 92.8%, 95.1% in TAM, Silent TAM and neonates with no GATA1 mutations; Plog-rank=0.0262). ML-DS was diagnosed at a median age of 14 m (range 3-18 m) preceded in all cases by a fall in platelet count. No single risk factor at birth specifically predicted for ML-DS although all 6 neonates with TAM who developed ML-DS had a mutant GATA1 VAF of >15% and blasts >20% at birth. The DS neonate with Silent TAM had a VAF of 2.5% and 4% blasts; this neonate was the only one of the cohort with a partial trisomy 21. Conclusion: Acquired N-terminal mutations in GATA1 are very frequent in neonates with DS and most probably occur or expand in the 3rd trimester; in the majority of cases mutant GATA1 clones are very small, clinically silent, resolve spontaneously and confer an extremely low risk of ML-DS. DisclosuresVyas:Jazz Pharmaceuticals: Speakers Bureau; Celgene Corporation: Speakers Bureau.

Clinical features of 35 Down syndrome patients with transient abnormal myelopoiesis at a single institution

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 (> 2mg/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.

Cases of transient abnormal myelopoiesis

Transient abnormal myelopoiesis (TAM) is a unique hematological syndrome specific for neonates with Down syndrome. Clinical and hematological manifestations of ТАМ are similar manifestations of acute leukemia, but they may resolve spontaneously by few weeks/months after birth. Summation trisomy 21 and GATA1 mutation in blast clone is a required element for development TAM. Presentation of this syndrome occurs in the first days of life; clinical manifestations may be absent (“silent” TAM) or even lead to death of fetus and neonate. The main interest in the study of this issue is the fact that after spontaneous regression there in 20% of cases at the age of 3–4 years developing acute megakaryoblastic leukaemia (AMKL). The basic transformation factors TAM to AMKL are unknown. In this article we represent 6 cases of TAM identified in Dmitry Rogachev National Research Center for Pediatric Hematology, Oncology, and Immunology from 2012 to 2019. Parents of these patients gave their agreement to use personal data in research and publications.

新生児遷延性肺高血圧症（PPHN）を合併した一過性骨髄異常増殖症候群（TAM）の4例

新生児遷延性肺高血圧症（PPHN）を合併した一過性骨髄異常増殖症候群（TAM）の4例

GATA1 and cooperating mutations in myeloid leukaemia of Down syndrome.

Myeloid leukaemia of Down syndrome (ML-DS) is an acute megakaryoblastic/erythroid leukaemia uniquely found in children with Down syndrome (constitutive trisomy 21). It has a unique clinical course, being preceded by a pre-leukaemic condition known as transient abnormal myelopoiesis (TAM), and provides an excellent model to study multistep leukaemogenesis. Both TAM and ML-DS blasts carry acquired N-terminal truncating mutations in the erythro-megakaryocytic transcription factor GATA1. These result in exclusive production of a shorter isoform (GATA1s). The majority of TAM cases resolve spontaneously without the need for treatment; however, around 10% acquire additional cooperating mutations and transform to leukaemia, with differentiation block and clinically significant cytopenias. Transformation is driven by the acquisition of additional mutation(s), which cooperate with GATA1s to perturb normal haematopoiesis.

Predictive Factors of the Development of Leukemia in Patients with Transient Abnormal Myelopoiesis and Down Syndrome: The Jccg Study JPLSG TAM-10

Introduction: Transient abnormal myelopoiesis (TAM) in neonates with Down syndrome (DS) is characterized by the transient appearance of blast cells that harbor somatic GATA1 gene mutation. Although most patients show spontaneously resolution without therapeutic interventions, approximately 20% of TAM cases result in early deaths within 9 months and 20% of survivors develop acute megakaryoblastic leukemia (AMKL) within 4 years. Although the risk factors associated with early deaths are known, the definite clinical predictive indicators of AMKL onset in patients with TAM remain unclear. Therefore, we analyzed 167 TAM patients with DS enrolled in the TAM-10 prospective observational study conducted by the Japan Pediatric Leukemia/Lymphoma Study Group (JPLSG) to determine the clinical characteristics of TAM and predictive factors of leukemia development. Patients and Methods: Between May 2011 and February 2014, 167 neonates (89 boys and 78 girls) diagnosed with TAM were prospectively registered in the TAM-10 study. Somatic GATA1 gene mutations were confirmed in 163 (98%) patients using Sanger and/or next-generation sequencing. Minimal residual disease using flow cytometry (FCM-MRD; cut-off level, ≥0.1%) was monitored at 1 (n = 133) and 3 months (n = 104). Results: Median (range) gestational age, birth body weight, white blood cell (WBC) count, and percentage of blasts at diagnosis were 37 (29-40) weeks, 2,612 (1,066-3714) g, 38.3 (2.4-478.7) × 109 cells/L, and 37% (0.5%-95.5%), respectively. Systemic edema and organ hemorrhage was observed in 31/167 (19%) and 14/167 (8%) patients, respectively; 68/167 (41%) patients received some therapeutic interventions, including low-dose cytarabine (LDCA; n = 52), exchange blood transfusion (n = 20), and systemic steroid therapy (n = 31). Early death (&lt;9 months of age) occurred in 22/167 (13%) patients. In multivariate analysis, early death was significantly associated with a high WBC count [≥100 × 109 cells/L; HR (95% CI) = 5.329 (2.194-12.945), P &lt; 0.001] and systemic edema [HR (95% CI) = 8.073 (3.130-20.823), P &lt; 0.001]. Subgroup analysis in patients with such high WBC count (n = 36) showed that LDCA therapy significantly improved survival [1-year OS (95% CI) = 78.3% (55.4-90.3; n = 23) vs. 38.5% (14.1-62.8; n = 13); P = 0.009]. Among 145/167 patients without early death, 28 (19%) developed AMKL. FCM-MRD positivity at 1 month [positive, n = 107; negative, n = 26; cumulative incidence ratio (CIR) (95% CI) = 25.2% (17.3-33.9%) vs 3.8% (0.3%-16.8%), P = 0.022] and 3 months (positive, n = 20; negative, n = 84; CIR (95% CI), 45.0% (22.3%-65.4%) vs. 16.0% (9.0%-24.8%), P = 0.002] was significantly associated with leukemia development. However, other clinical covariates, including sex, birth weight, gestational age, WBC count, blast percentage, and GATA1 gene mutational types, could not predict AMKL development. Considering their severe clinical conditions, 13/31 (42%) patients who received systemic steroid therapy died before AMKL development; interestingly, none of the remaining 18 patients developed AMKL but they showed significantly lower CIR than those who did not receive this therapy [CIR (95% CI), 0% vs. 19.4% (10.9%-29.6%), P = 0.010]. Other therapeutic interventions, including LDCA and exchange blood transfusion, were not associated with AMKL development. Conclusion: FCM-MRD positivity at 1 month and 3 months might be a useful marker to predict leukemia development in patients with TAM. Although LDCA therapy significantly decreased the rate of early deaths, it did not suppress leukemia development. Interestingly, systemic steroid therapy might suppress leukemia development. These results pave the way to design clinical trials for developing MRD-directed leukemia prevention therapy for patients with TAM. Disclosures No relevant conflicts of interest to declare.

Transient Abnormal Myelopoiesis in a Neonate without Down Syndrome

Transient abnormal myelopoiesis (TAM) also known as transient myeloproliferative disorder (TMD), a unique transient neonatal preleukaemic disorder characterized by clonal proliferation of megakaryoblasts, has been usually described to be associated with Down syndrome neonates. However, there are case reports of it occurring in neonates without Down phenotype, who are either mosaic for trisomy 21 or have trisomy 21 restricted to leukemic clone. This case report presents a case of TAM in a phenotypically normal neonate who presented in respiratory distress with features of tumour lysis syndrome (TLS) immediately after birth who was treated symptomatically and had spontaneous remission within three months.

Sometimes it is better to wait: First Italian case of a newborn with transient abnormal myelopoiesis and a favorable prognosis.

Congenital leukemia is rare disease with an incidence of one to five cases per million births. Transient abnormal myelopoiesis (TAM), also called transient myeloproliferative disorder, is a pre-leukemia disorder that may occur in Down syndrome (DS) or non-DS infants. TAM may enter spontaneous remission; however, continual monitoring is required, as this disorder has been observed to develop into acute megakaryoblastic leukemia in 16–30% of cases. In the literature, 16 cases of TAM in non-DS infants have been reported. The case presented in the current study is, to the best of our knowledge, the first case of an Italian non-DS newborn presenting with clinical manifestations of acute leukemia at five days after birth, exhibiting a normal karyotype, trisomy 21 only in blast cells, and spontaneous remission. Chromosomal analyses on peripheral blood cells, bone marrow cells and dermal fibroblasts were conducted using a G-banding technique, and fluorescence in situ hybridization (FISH) was used to identify the critical regions of DS. Amplification of GATA binding protein 1 (GATA1) exon 2 genomic DNA was performed using polymerase chain reaction. Cytogenetic analysis of 50 peripheral blood cells and dermal fibroblasts from the patient revealed a normal karyotype: 46, XX. Conversely, cytogenetic analysis of the patient's bone marrow revealed an abnormal karyotype 47, XX+21. In order to investigate this result, FISH was performed, which identified the presence of three signals in 70% of the cells and two signals in 30% of bone marrow cells. GATA1 sequencing revealed the substitution of a single base (c.150delG) in exon 2. Seven months after the initial analysis, FISH and cytogenetic analyses of the stimulated/unstimulated peripheral blood cells and bone marrow cells were performed, revealing that each exhibited diploid signals, as observed in a normal karyotype.

Transient Abnormal Myelopoiesis and AML in Down Syndrome: an Update.

Children with constitutional trisomy 21 (Down syndrome (DS)) have a unique predisposition to develop myeloid leukaemia of Down syndrome (ML-DS). This disorder is preceded by a transient neonatal preleukaemic syndrome, transient abnormal myelopoiesis (TAM). TAM and ML-DS are caused by co-operation between trisomy 21, which itself perturbs fetal haematopoiesis and acquired mutations in the key haematopoietic transcription factor gene GATA1. These mutations are found in almost one third of DS neonates and are frequently clinically and haematologcially ‘silent’. While the majority of cases of TAM undergo spontaneous remission, ∼10 % will progress to ML-DS by acquiring transforming mutations in additional oncogenes. Recent advances in the unique biological, cytogenetic and molecular characteristics of TAM and ML-DS are reviewed here.

Elevated delta OD 450 due to transient abnormal myelopoiesis in a Down syndrome fetus with hepatosplenomegaly on ultrasound

Transient abnormal myelopoiesis (TAM) is a relatively common finding in children with Down syndrome but has also been diagnosed prenatally, most often presenting with fetal hepatosplenomegaly. We report a case of TAM with hepatosplenomegaly found on ultrasound and associated with an increased amniotic fluid Δ OD 450 value. TAM is most commonly transient but can be associated with fatality and therefore should be considered in the differential diagnosis when fetal hepatosplenomegaly is found on ultrasound. Amniocentesis with chromosomal analysis and a Δ OD 450 may aid in diagnosing TAM and predicting the severity of the liver involvement.

Down syndrome and GATA1 mutations in transient abnormal myeloproliferative disorder: mutation classes correlate with progression to myeloid leukemia

AbstractTwenty percent to 30% of transient abnormal myelopoiesis (TAM) observed in newborns with Down syndrome (DS) develop myeloid leukemia of DS (ML-DS). Most cases of TAM carry somatic GATA1 mutations resulting in the exclusive expression of a truncated protein (GATA1s). However, there are no reports on the expression levels of GATA1s in TAM blasts, and the risk factors for the progression to ML-DS are unidentified. To test whether the spectrum of transcripts derived from the mutant GATA1 genes affects the expression levels, we classified the mutations according to the types of transcripts, and investigated the modalities of expression by in vitro transfection experiments using GATA1 expression constructs harboring mutations. We show here that the mutations affected the amount of mutant protein. Based on our estimates of GATA1s protein expression, the mutations were classified into GATA1s high and low groups. Phenotypic analyses of 66 TAM patients with GATA1 mutations revealed that GATA1s low mutations were significantly associated with a risk of progression to ML-DS (P < .001) and lower white blood cell counts (P = .004). Our study indicates that quantitative differences in mutant protein levels have significant effects on the phenotype of TAM and warrants further investigation in a prospective study.

Distinctive Hematological Abnormalities and GATA1 Mutation Spectra In East Asian Neonates and Children with Down Syndrome

AbstractAbstract 4837 Background:Many hematological abnormalities have been reported during the neonatal period in infants with Down syndrome (DS). Neonates with DS are predisposed to developing transient abnormal myelopoiesis (TAM) and acute megakaryblastic leukemia (AMKL). However, there is a paucity of data on hematological aberrations and GATA1 gene mutations in neonates with DS in East Asian populations. We therefore investigated the spectrum of hematological abnormalities in infants and children with DS in one such population, and analyzed the frequency and pathophysiological role of GATA1 mutations in DS-TAM and DS-AMKL in this group. Patients and Methods:A total 148 patients with DS were identified from January 2000 to December 2009. Of these, 109 had had blood drawn for a complete blood count (CBC) with differential. There were 37 neonates (°Â4 weeks of age), 55 children (<18 years of age), and 17 adults °Ã 18 years of age) in the study. A comprehensive molecular study of the GATA1 gene was performed using PCR, RT-PCR and direct sequencing for all six exons (7,757 bp) and cDNA sequence of GATA1 gene. Results:Thrombocytopenia was most common hematological abnormality (35%) in the neonates. Leukocytosis and polycythemia were each detected in 4 cases (11%). Blasts were identified in the differential count of 6 (16%) neonates. Of the 55 children with DS, 11 (20%) had thrombocytopenia, 10 (18%) had anemia, and 7 (13%) had neutropenia (< 1,500/uL). There were also 4 (7%) cases of AMKL and 2 (4%) cases of acute lymphoblastic leukemia in the children with DS. GATA1 mutations were identified in all of the TAM samples and in 2 of the 3 AMKL samples, but were not detected in the 1 remission sample or the 2 samples from normal DS children. Conclusions:East Asian DS neonates showed distinctive hematological abnormalities such as uncommon neutrophilia, relatively common neutropenia, and increased prevalence of TAM compared with reports from Western countries. The GATA1 mutation analysis may offer the potential to accelerate and refine the diagnosis of TAM and AMKL, and to accurately measure the kinetics of the mutant GATA1 clone as a tool for minimal residual disease measurement because virtually all cases of TAM and AMKL harbored this mutation. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Transient abnormal myelopoiesis (TAM) における肝線維化マーカーの検討

Transient abnormal myelopoiesis (TAM) is usually a self-limiting myeloproliferative disorder observed in approximately 10% of newborn infants with Down syndrome. However, progressive liver fibrosis may occur in patients with TAM and is often lethal. We investigated the utility of the serum levels of hyaluronic acid (HA) and N-terminal peptide of III procollagen (P-III-P) as markers of liver fibrosis and indication for chemotherapy. We reviewed 4 cases of TAM retrospectively. HA levels were more than one hundred times as high as the upper limit of the normal range in 2 patients, one of whom died from gastrointestinal bleeding. His HA and P-III-P had increased up to 18,800 U/ml and 26.2 ng/ml, respectively, just before he died. Another patient's serum HA and P-III-P increased to 6,100 U/ml and 12.8 ng/ml, respectively, however his liver fibrosis resolved with low-dose cytosine arabinoside treatment after exchange transfusion during his clinical course. We suggest that serum HA is useful as a marker of liver fibrosis and a prognostic indicator for chemotherapy in patients with TAM. Early treatment including both exchange transfusion and chemotherapy should be considered for patients presenting with extremely high or an elevating tendency of their HA serum levels.

Prenatal Diagnosis of Transient Abnormal Myelopoiesis in a Down Syndrome Fetus

We report a case of transient abnormal myelopoiesis in a Down syndrome fetus diagnosed at 28+3 weeks of gestation that rapidly progressed to intrauterine death 10 days later. Fetal hepatosplenomegaly with cerebral ventriculomegaly, although not specific, may be a suggestive finding of Down syndrome with transient abnormal myelopoiesis. Prompt fetal blood sampling for liver function test and chromosomal analysis are mandatory for early detection and management.