Transient Abnormal Myelopoiesis Research Articles

Three Cases of Down Syndrome with Transient Abnormal Myelopoiesis who Underwent Liver Biopsy before Induction of Low-Dose Cytarabine.

Among patients with transient abnormal myelopoiesis (TAM) associated with Down syndrome, approximately 20% die within 6 months from multiorgan failure, especially liver fibrosis. We experienced three children with TAM who had low white blood cell counts but increased bilirubin levels. Here, we discuss the detailed clinical courses of these patients, including the pathological findings of liver biopsies. Our cases, together with previous literature, suggest that liver biopsy can be performed safely and provides useful information, especially regarding disease activities, and that low-dose cytarabine is a reasonable option to prevent early death in TAM patients with liver dysfunction.

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.

Clinical practice-latest insights in optimizing the care of children with Down syndrome.

An essential part of the care of children with Down syndrome is secondary screening for comorbidity. It is well known that comorbidity frequently occurs in these children. A new update of the Dutch Down syndrome medical guideline was developed to create a sound evidence base for several of these conditions. We present the latest insights and recommendations from this Dutch medical guideline which are based on the most relevant literature currently available and developed with rigorous methodology. The main focus of this revision of the guideline was on obstructive sleep apnea and other airway problems and hematologic disorders, such as transient abnormal myelopoiesis, leukemia, and thyroid disorders. Conclusion:This is a short summaryof the latest insights and recommendations from the updated Dutch medical guideline for children with Down syndrome.

Leukemogenesis in infants and young children with trisomy 21.

Children with Down syndrome (DS) have a greater than 100-fold increased risk of developing acute myeloid leukemia (ML) and an approximately 30-fold increased risk of acute lymphoblastic leukemia (ALL) before their fifth birthday. ML-DS originates in utero and typically presents with a self-limiting, neonatal leukemic syndrome known as transient abnormal myelopoiesis (TAM) that is caused by cooperation between trisomy 21-associated abnormalities of fetal hematopoiesis and somatic N-terminal mutations in the transcription factor GATA1. Around 10% of neonates with DS have clinical signs of TAM, although the frequency of hematologically silent GATA1 mutations in DS neonates is much higher (~25%). While most cases of TAM/silent TAM resolve without treatment within 3 to 4 months, in 10% to 20% of cases transformation to full-blown leukemia occurs within the first 4 years of life when cells harboring GATA1 mutations persist and acquire secondary mutations, most often in cohesin genes. By contrast, DS-ALL, which is almost always B-lineage, presents after the first few months of life and is characterized by a high frequency of rearrangement of the CRLF2 gene (60%), often co-occurring with activating mutations in JAK2 or RAS genes. While treatment of ML-DS achieves long-term survival in approximately 90% of children, the outcome of DS-ALL is inferior to ALL in children without DS. Ongoing studies in primary cells and model systems indicate that the role of trisomy 21 in DS leukemogenesis is complex and cell context dependent but show promise in improving management and the treatment of relapse, in which the outcome of both ML-DS and DS-ALL remains poor.

Mechanism of KIT gene regulation by GATA1 lacking the N-terminal domain in Down syndrome–related myeloid disorders

Children with Down syndrome (DS) are at high risk of transient abnormal myelopoiesis (TAM) and myeloid leukemia of DS (ML-DS). GATA1 mutations are detected in almost all TAM and ML-DS samples, with exclusive expression of short GATA1 protein (GATA1s) lacking the N-terminal domain (NTD). However, it remains to be clarified how GATA1s is involved with both disorders. Here, we established the K562 GATA1s (K562-G1s) clones expressing only GATA1s by CRISPR/Cas9 genome editing. The K562-G1s clones expressed KIT at significantly higher levels compared to the wild type of K562 (K562-WT). Chromatin immunoprecipitation studies identified the GATA1-bound regulatory sites upstream of KIT in K562-WT, K562-G1s clones and two ML-DS cell lines; KPAM1 and CMK11-5. Sonication-based chromosome conformation capture (3C) assay demonstrated that in K562-WT, the − 87 kb enhancer region of KIT was proximal to the − 115 kb, − 109 kb and + 1 kb region, while in a K562-G1s clone, CMK11-5 and primary TAM cells, the − 87 kb region was more proximal to the KIT transcriptional start site. These results suggest that the NTD of GATA1 is essential for proper genomic conformation and regulation of KIT gene expression, and that perturbation of this function might be involved in the pathogenesis of TAM and ML-DS.

A Bone Marrow Mimetic 3D Co-Culture Model for Ex Vivo drug Testing of Down Syndrome-Myeloid Leukemia Cells

Children with Down syndrome are at elevated risk (10-20-fold) for the development of leukemia. The DS-myeloid leukemia (DS-ML) treatment relies largely on low-dose cytarabine (Ara-C). Despite the favorable outcome, there is 20% mortality rate associated with DS-ML. There is no targeted therapy so far for the patients who fail to respond to Ara-C treatment. Majority of clinical trials exploring investigational drugs for AML exclude DS patients because of differential drug sensitivity. Patient-derived xenograft models of DS-ML are limited, because of low sample availability and low success of engraftment. Therefore, an ex vivo drug testing model for DS-ML that can avoid the pitfalls of 2D culture system is a powerful tool to test novel therapies and understand the drug response mechanisms. To overcome the shortfalls of the previous in vitro drug testing systems for AML, we developed a 3D model that facilitates efficient interaction between leukemia cells with bone marrow mesenchymal stem cells (BM-MSCs) in a 3D microenvironment mimicking the extracellular matrix (ECM) components and modulus of BM. We generated pediatric BM-MSC lines from donor BM aspirates by their ability to adhere to tissue culture plastic. The immunophenotype analysis revealed that BM-MSC lack the expression of CD34 and CD45 but express CD90, CD44, CD105, CD73, CD166 and CD146. MSCs retained the potential of differentiation into the osteogenic, chondrogenic and adipogenic lineages. In addition to the cellular component, the BM microenvironment consists of various ECM proteins that contribute to the mechanics of the BM, and have profound effect on cellular phenotype and metabolism. PEG provides a blank slate for analyzing the peptide specific cellular responses, and can be further tuned to specify 3D architecture. The hydrogel-based 3D gel system that we developed for the generation of 3D model for transient abnormal myelopoiesis (Sidhu et al., Biomater Sci, 9:6266, 2021) was further tuned by the incorporation of BM mimetic peptides with composition and ratio determined by a proteomics study using human BM (Jansen et al., bioRxiv, 2018). To develop a BM model for drug testing, PEG gels containing BM-ECM mimicking peptides were used to encapsulate CMK cells alone and in co-culture with BM-MSCs. CMK cells treated with 0.5µM of Ara-C showed higher viability in co-culture (73% ± 12%) when compared to monoculture (52% ± 5%) (Figure 1A; bars 3 & 4; p*= 0.012). Similar to Ara-C, treatment with 0.75µM Azacitidine (Aza, a DNA hypomethylating agent) had a significantly higher viability in co-culture (90% ± 5%) compared to monoculture (74% ± 7%) (Figure 1A; bars 5 & 6; p*= 0.031). The chemoprotection of BM-MSCs against individual drug (Ara-C and Aza) was overridden by the sequential therapy with 0.75µM Aza for 24h, followed by 48h treatment with 0.5µM Ara-C under BM mimetic conditions. Compared to Ara-C alone treatment, cell viability was significantly lower in sequential therapy, with 39% (Figure 1A; bars 4 & 7; p#< 0.01) lower cell viability. Similarly, the sequential therapy reduced the cell viability by 56% when compared to Aza alone treatment (Figure 1C; Bars 6 and 7; p$< 0.01). This implies that Aza treatment can sensitize DS-ML cells to Ara-C treatment to disrupt the chemoprotective environment provided by BM-MSCs. In vitro megakaryocytic DS-ML cells harboring GATA1 and STAG2 mutations (T21-G1-S40) showing DS-ML characteristics were generated as described previously (Barwe et al., Cells, 11:628, 2022). The effect of Aza sensitization was tested in megakaryocytic lineage expanded T21-G1-S40 cells. Similar to CMK, the sequential treatment of T21-G1-S40 megakaryocytic cells show reduced cell viability (62% ± 6%; Figure 1B, bar 4) than the individual treatment with Ara-C (73% ± 7%; Figure 1B, bar2) and Aza (92% ± 6%; Figure 1B, bar 3). In summary, we established a synthetic 3D BM mimetic ex-vivo model consisting of the ECM components, mechanics and one of the key cellular components (MSCs) of BM microenvironment. The pediatric BM-MSCs induce chemoprotection to cytotoxic drugs in DS-ML cells. This chemoprotection can be overridden by the use of epigenetic modifier azacitidine. This study provides proof of principle for establishing a BM mimicking ex vivo model that can be utilized for high throughput drug screening. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

FIVE INTERFERON RECEPTOR TRIPLICATES: A UNIQUE CASE OF HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS IN A DOWN SYNDROME PATIENT

<h3>Introduction</h3> Down Syndrome (DS) is recognized as a mild interferonopathy with features of autoimmunity, developmental delays and brain calcifications explained by triplicates of four of the six interferon receptors (IFNAR1, IFNAR2, IFNGR2, and IL10RB) found on chromosome 21. We describe hemophagocytic lymphohistiocytosis (HLH) in a DS patient who was found to have a second copy number gain encompassing IFNGR1. <h3>Case Description</h3> An ex 35-week male with a history of DS and transient abnormal myelopoiesis in the newborn period presented at 10 months of age with recurrent fever, lymphadenopathy and splenomegaly. He met criteria for HLH with anemia, hyperferritinemia, elevated soluble CD25, elevated fibrinogen and a cervical lymph node biopsy showing evidence of hemophagocytosis. Evaluation for underlying triggers was unremarkable. Given a disproportionately elevated interleukin-18 (148,566pg/mL) and S100A12 (26,911ng/mL) compared to CXCL9 (161pg/mL), targeted treatment with anakinra was initiated. The patient defervesced and laboratory findings improved. A primary immunodeficiency gene panel revealed copy number variants consistent with chromosome 21, along with a duplication of <i>IFNGR1</i> gene located on chromosome 6. A post-natal microarray confirmed trisomy 21 and revealed a duplication on chromosome 6p23.3 involving the <i>IFNGR1</i> gene. His type I interferon gene signature (IGS) was only slightly elevated while on therapy. <h3>Discussion</h3> DS has been established to have both elevated Type I and II IGS in the setting of 4/6 interferon receptor gene triplicates. Our patient has the unique overexpression of the IFNGR1 gene as well, likely contributing to his HLH-like presentation.

ALL-124 Outcome of Acute Leukemia in Down Syndrome: A Retrospective Experience of Ain Shams Pediatric Oncology Over a Decade

Children with Down syndrome are at an elevated risk of acute leukemia, namely myeloid leukemia (ML-DS) and acute lymphoblastic leukemia (DS-ALL), though the higher risk of developing leukemia remains largely unclear. This malignancy is frequently preceded by transient abnormal myelopoiesis, which is self-limited, as recently published in our center. Acute megakaryoblastic leukemia (M7) is a rare subtype of pediatric acute myeloid leukemia with better outcomes in patients with Down syndrome. Ain Shams genetic center, established in 1964, serves more than 200 new Down syndrome patients annually. The pediatric oncology center, started in 1974, serves nearly 100 new acute leukemia patients yearly. The main outcome was to evaluate the prognostic significance of cytogenetic abnormalities and minimal residual disease status as determined by flow cytometer after induction. We retrospectively analyzed the data of 30 patients with a diagnosis of ML-DS and ALL-DS at Ain Shams over the last decade (2010-2020). Sixty percent of the patients were female, and ages ranged from 9 to 92 months. Diagnosis was either ALL (n=7) or AML (n=23), including M7 (n=5). Event-free survival at 2 years was 70%, whereas 10% died during induction; the cumulative incidence of relapse at 2 years (n=5) was 15%, and one patient was excluded from the survival analysis. Of the 30 patients, half had cytogenetic abnormalities; none of these had an effect on the outcome. In addition, one-third of patients had minimal residual disease <0.1% after induction, but the difference did not reach statistical significance. Acute leukemia, whether acute megakaryoblastic leukemia or not, had an improving response over the last decade in children with Down syndrome compared with those without, with no clearly defined prognostic factors.

Down syndrome-associated transient abnormal myelopoiesis with placental involvement.

A 2-day-old Down syndrome (DS) neonate born at 35 weeks 5 days presented with leukocytosis and blasts showing cytoplasmic blebs (Panel1×600). By flow-cytometry, blasts were positive for CD34, CD61 and CD71 consistent with megakaryoblasts. Based on fetoplacental circulation (Figure), blasts lodged in the umbilical cord, chorionic plate, villi and membranes (Panels 2–5, H&E×100). Megakaryoblasts were generally confined to vascular lumina, but they infiltrated their walls (Panel 2 right, H&E×100). Immunohistochemically, blasts expressed CD61 (Panels 2,4,5×100 objective). Leukocytosis and increased blasts resolved within two weeks. These findings are consistent with DS-associated transient abnormal myelopoiesis (TAM) with placental involvement. Somatic mutations of GATA1 are involved in the pathogenesis of DSTAM. GATA1 gene is necessary for the development of megakaryocytic lineages. Trisomy 21 perturbs fetal hematopoiesis, providing the context for: transformation of these fetal hematopoietic cells by acquired mutations in the GATA1 gene to produce DSTAM. Eighty percent of DSTAM cases resolve spontaneously within three months, coinciding with the transition of hematopoiesis from fetal liver to bone marrow. Fetal and maternal malignancies can cross and metastasize to the placenta. In fetal metastasis, tumor cells stay confined to the fetal vessels, while, in maternal malignancies, cells infiltrate the peri-villous(maternal) space (Panel 6*). Patient's parental verbal and written consent was received. Figure: Blasts showing cytoplasmic blebs (Panel1 × 600). Blasts lodged in the umbilical cord, chorionic plate, villi and membranes (Panels 25, H&E × 100). Megakaryoblasts were generally confined to vascular lumina, but they infiltrated their walls (Panel 2 right, H&E × 100). Immunohistochemically, blasts expressed CD61 (Panels 2,4,5 × 100 objectiv). Peri-villous (maternal) space is spared (Panel 6) Literature review on placenta involved by TAM show in the majority of cases, peripheral blood leukocytosis exceeded 100 000/μL and blast counts ranged from 23% to 95%. A consistent finding was also the presence of circulating blast cells in the umbilical cord and chorionic villous vasculature. Leukocytosis with left-shifted hematopoietic elements and myeloid blasts can be seen within vessels of the umbilical cord, chorionic plate, and chorionic villi. Myeloid blasts are generally confined to vascular lumina, but they can infiltrate the vascular wall and stroma to varying degrees. The differential diagnoses are broad. It includes acute villitis, intervillositis, microabscesses caused by listeriosis and E coli, and enlarged, hypercellular chorionic villi with lymphoplasmacytic infiltrations, and large inclusion cells in cytomegalovirus infection, all of which can mimic a leukemoid reaction or TAM. We would like to thank Dr Herrmann for funding this study. The authors have declared no conflict of interest. This case followed Loma Linda University and patient ethics. The data that support the findings of this study are available from the corresponding author upon reasonable request.

Advances in molecular characterization of myeloid proliferations associated with Down syndrome.

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 multi-center studies would be helpful to advance molecular characterization of these diseases at different stages of development and progression.

Why Is Health Care for Children with Down Syndrome So Crucial from the First Days of Life? A Retrospective Cohort Study Emphasized Transient Abnormal Myelopoiesis (TAM) Syndrome at Three Centers.

Down syndrome (DS) is a common genetic disorder and is associated with an increased likelihood of many diseases, including defects of the heart, genitourinary system, gastrointestinal tract, and oncological diseases. The aim of this study was to analyze medical problems occurring in newborns with DS and to create a basic diagnostic and therapeutic algorithm intended primarily for neonatologists, pediatricians, family physicians, and physicians of other specialties caring for children with DS. Over a 5-year period, the medical records of 161 neonates with Down syndrome from four neonatology departments in Poznan, Poland, were examined. After applying exclusion criteria, 111 patients were analyzed. Data obtained from medical history included sex, week of gestation, birth weight, APGAR score, clinical symptoms, peripheral blood count with smear, and clinical features such as jaundice, hemorrhagic diathesis, ascites, hepato- or splenomegaly, pericardial or pleural effusion, respiratory failure, and other rare transient signs of abnormal myelopoiesis: fetal edema, hepatic fibrosis, renal failure, and rush. In the study group, 8% of children with Down syndrome were diagnosed with a heart and 1.8% with a genitourinary defect. Transient abnormal myelopoiesis syndrome (Transient abnormal myelopoiesis (TAM)) was found in 10% of newborns with DS. A blood count with blood smear, cardiology consultation with echocardiography, and an abdominal ultrasound should be performed in the first few days after birth in all newborns with Down syndrome. If this is not possible and the child’s condition is stable, these tests can be performed within 2–3 months after birth.

Germline GATA1 exon 2 mutation associated with chronic cytopenia and a non-down syndrome transient abnormal myelopoiesis with clonal trisomy 21

Germline GATA1 exon 2 mutation associated with chronic cytopenia and a non-down syndrome transient abnormal myelopoiesis with clonal trisomy 21

A sensitive and inexpensive high-resolution melting-based testing algorithm for diagnosis of transient abnormal myelopoiesis and myeloid leukemia of Down syndrome.

Patients with Down syndrome (DS) are commonly affected by a pre-leukemic disorder known as transient abnormal myelopoiesis (TAM). This condition usually undergoes spontaneous remission within the first 2months after birth; however, in children under 5, 20%-30% of cases evolve to myeloid leukemia of Down syndrome (ML-DS). TAM and ML-DS are caused by co-operation between trisomy 21 and acquired mutations in the GATA1 gene. Currently, only next-generation sequencing (NGS)-based methodologies are sufficiently sensitive for diagnosis in samples with small GATA1 mutant clones (≤10% blasts). Alternatively, this study presents research on a new, fast, sensitive, and inexpensive high-resolution melting (HRM)-based diagnostic approach that allows the detection of most cases of GATA1 mutations, including silent TAM. The algorithm first uses flow cytometry for blast count, followed by HRM and Sanger sequencing to search for mutations on exons 2 and 3 of GATA1. We analyzed 138 samples of DS patients: 110 of asymptomatic neonates, 10 suspected of having TAM, and 18 suspected of having ML-DS. Our algorithm enabled the identification of 33 mutant samples, among them five cases of silent TAM (5/110) and seven cases of ML-DS (7/18) with blast count ≤10%, in which GATA1 alterations were easily detected by HRM. Depending on the type of genetic variation and its location, our methodology reached sensitivity similar to that obtained by NGS (0.3%) at a considerably reduced time and cost, thus making it accessible worldwide.

Clonal Myeloproliferative Disorders in Patients with Down Syndrome-Treatment and Outcome Results from an Institution in Argentina.

Simple SummaryAround 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.

Transient abnormal myelopoiesis at birth with Down syndrome: A rare case report

Down syndrome is associated with rare hematological disorder like Transient abnormal myelopoiesis in infants. We report a case of preterm female baby with low birth weight born to 33 year old mother who is G2A1 at 34 weeks of gestation. Antenatal checkup revealed intermediate risk for Down syndrome. On the first day of birth CBC showed high WBC count of127000/ mm3 and peripheral smear showed 13% of blast and the total count gradually decreased to normal of 20000/ mm3 over a period of one month. The baby succumbed to death due to Congestive cardiac failure and late onset sepsis.

Accelerated epigenetic aging in newborns with Down syndrome.

Accelerated aging is a hallmark of Down syndrome (DS), with adults experiencing early‐onset Alzheimer's disease and premature aging of the skin, hair, and immune and endocrine systems. Accelerated epigenetic aging has been found in the blood and brain tissue of adults with DS but when premature aging in DS begins remains unknown. We investigated whether accelerated aging in DS is already detectable in blood at birth. We assessed the association between age acceleration and DS using five epigenetic clocks in 346 newborns with DS and 567 newborns without DS using Illumina MethylationEPIC DNA methylation array data. We compared two epigenetic aging clocks (DNAmSkinBloodClock and pan‐tissue DNAmAge) and three epigenetic gestational age clocks (Haftorn, Knight, and Bohlin) between DS and non‐DS newborns using linear regression adjusting for observed age, sex, batch, deconvoluted blood cell proportions, and genetic ancestry. Targeted sequencing of GATA1 was performed in a subset of 184 newborns with DS to identify somatic mutations associated with transient abnormal myelopoiesis. DS was significantly associated with increased DNAmSkinBloodClock (effect estimate = 0.2442, p < 0.0001), with an epigenetic age acceleration of 244 days in newborns with DS after adjusting for potential confounding factors (95% confidence interval: 196–292 days). We also found evidence of epigenetic age acceleration associated with somatic GATA1 mutations among newborns with DS (p = 0.015). DS was not associated with epigenetic gestational age acceleration. We demonstrate that accelerated epigenetic aging in the blood of DS patients begins prenatally, with implications for the pathophysiology of immunosenescence and other aging‐related traits in DS.

Life threatening congenital hydropericardium in a newborn with Down syndrome, transient abnormal myelopoiesis, Hirschsprung disease and a ventricular septal defect.

Life threatening congenital hydropericardium in a newborn with Down syndrome, transient abnormal myelopoiesis, Hirschsprung disease and a ventricular septal defect.

TMD in Down Syndrome

Down syndrome is the most common autosomal trisomy with an incidence of 1 in 700 to 800 live births. 1 Hematologic abnormalities are common in Down syndrome. 10% of infants with Down syndrome develop an abnormal myeloproliferative disorder called transient abnormal myelopoiesis (TAM). 2 It occurs because of uncontrolled proliferation of myeloblasts in peripheral blood and bone marrow and is characterized by the presence of GATA-1 mutation along with trisomy 21. The majority of the cases show spontaneous remission without the need for chemotherapy, and only supportive care is required for such cases. We present a newborn with Down syndrome who developed TAM within the first week of life and showed spontaneous remission with supportive care.

Transient abnormal myelopoiesis in Down syndrome: Experience of long term follow up from a single tertiary center in Thailand

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

A Nonimmune Hydrops Case.

A Nonimmune Hydrops Case.