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Research on Down Syndrome (DS)

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DS is one of many Research, Condition, and Disease Categories (RCDC) that NIH studies. NIH's research portfolio on DS includes efforts to understand all aspects of the condition, including related health problems and health outcomes. Visit the RCDC website for spending estimates on DS research . You can also review a listing of all DS projects funded by NIH .

In 2018, NIH launched the INCLUDE (INvestigation of Co-occurring conditions across the Lifespan to Understand Down syndromE) Project , an NIH-wide effort focused on understanding the health needs of people with DS and their families. The INCLUDE Project serves as an umbrella for coordinating DS research across NIH and the DS Consortium membership.

Visit INCLUDE Project: Funding to find current and past research funding opportunities, projects funded through the INCLUDE Project, and IC research priorities related to DS.

The NIH DS Working Group, DS Consortium members, and organizations and agencies with an interest in DS contributed comments and input to the INCLUDE/DS Research Plan , published in 2020. The plan will help NIH and the DS Consortium coordinate DS research resources and meet INCLUDE Project research goals.

In addition to the INCLUDE Project, these NIH-funded ongoing activities study aspects of DS:

• Eunice Kennedy Shriver Intellectual and Developmental Disabilities Research Centers (Led by NICHD)
• DS-Connect ® : The Down Syndrome Registry (Led by NICHD)
• Alzheimer's Biomarkers Consortium of Down Syndrome (ABC-DS) (Led by NIA)
• PubMed Search Results for all articles with keyword "Down syndrome"

DS Research from Other Consortium Members

Some members of the DS Consortium also conduct research on DS, while others focus on providing services and support to people with DS and their families. Visit the following DS Consortium member websites to learn about their DS-related research:

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Article Contents

Introduction, recent advances in understanding phenotypes associated with ds, recent advances in therapy and future prospects, acknowledgements.

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Down syndrome—recent progress and future prospects

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Frances K. Wiseman, Kate A. Alford, Victor L.J. Tybulewicz, Elizabeth M.C. Fisher, Down syndrome—recent progress and future prospects, Human Molecular Genetics , Volume 18, Issue R1, 15 April 2009, Pages R75–R83, https://doi.org/10.1093/hmg/ddp010

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Down syndrome (DS) is caused by trisomy of chromosome 21 (Hsa21) and is associated with a number of deleterious phenotypes, including learning disability, heart defects, early-onset Alzheimer's disease and childhood leukaemia. Individuals with DS are affected by these phenotypes to a variable extent; understanding the cause of this variation is a key challenge. Here, we review recent research progress in DS, both in patients and relevant animal models. In particular, we highlight exciting advances in therapy to improve cognitive function in people with DS and the significant developments in understanding the gene content of Hsa21. Moreover, we discuss future research directions in light of new technologies. In particular, the use of chromosome engineering to generate new trisomic mouse models and large-scale studies of genotype–phenotype relationships in patients are likely to significantly contribute to the future understanding of DS.

Down syndrome (DS) is caused by trisomy of human chromosome 21 (Hsa21). Approximately 0.45% of human conceptions are trisomic for Hsa21 ( 1 ). The incidence of trisomy is influenced by maternal age and differs between populations (between 1 in 319 and 1 in 1000 live births are trisomic for Hsa21) ( 2 – 6 ). Trisomic fetuses are at an elevated risk of miscarriage, and people with DS have an increased risk of developing several medical conditions ( 7 ). Recent advances in medical treatment and social inclusion have significantly increased the life expectancy of people with DS. In economically developed countries, the average life span of people who are trisomic for Hsa21 is now greater than 55 years ( 8 ). In this review, we will discuss novel findings in the understanding of DS and highlight future important avenues of research.

Mouse models of Hsa21 trisomy and monosomy. Hsa21 (orange) is syntenic with regions of mouse chromosomes 16 (Mmu16, blue), 17 (Mmu 17, green) and 10 (Mmu10, grey). The Tc1 mouse model carries a freely segregating copy of Hsa21, which has two deleted regions, such that the model is trisomic for the majority of genes on Hsa21. The Dp1Yu, Ts65Dn, Ts1Cje and Ts1Rhr mouse models contain an additional copy of regions of mouse chromosome 16 that are syntenic with Hsa21, such that they are trisomic for a proportion of Hsa21 genes. The Ms1Rhr mouse model contains a deletion of a region of Mmu16; the Ms1Yah mouse model contains a deletion of a region of Mmu10. Hence, these models are monosomic for the genes in these deleted Hsa21 syntenic segments.

Box 1: What is a gene?

The definition of a gene has shifted over the past 100 years since it was first coined by Wilhelm Johannsen in 1909, based on the ideas of Mendel, de Vries, Correns and Tschermak. Their original theoretical definition of the gene being ‘the smallest unit of genetic inheritance’ remains the cornerstone of our understanding; however, the definition has grown with our knowledge of molecular biology. The gene has recently been defined as ‘a union of genomic sequences encoding a coherent set of potentially overlapping functional products’ ( 133 ). Splicing generates multiple transcripts from one gene. Moreover, exons from genes previously considered to be separate may be spliced together to generate novel transcripts ( 9 ). How to classify these fusion transcripts is a significant challenge. In addition, alternative transcription start sites that generate novel 5′ untranslated regions continue to be discovered, even for well-characterized genes ( 134 ). Although many of these novel transcripts are rare and their functional importance is not understood, our definition of a gene must encompass the observed diversity of the genome.

Trisomy of Hsa21 is associated with a small number of conserved features, occurring in all individuals, including mild-to-moderate learning disability, craniofacial abnormalities and hypotonia in early infancy ( 17 ). Although these phenotypes are always found in people with DS, the degree to which an individual is affected varies. Additionally, trisomy of Hsa21 is also associated with variant phenotypes that only affect some people with DS, including atrioventricular septal defects (AVSDs) in the heart, acute megakaryoblastic leukaemia (AMKL) and a decrease in the incidence of some solid tumours. This phenotypic variation is likely to be caused by a combination of environmental and genetic causes. Genetic polymorphisms in both Hsa21 and non-Hsa21 genes may account for much of this variation. Genome-wide association studies to identify these polymorphisms constitute a promising strategy to gain novel insights into the pathology of DS.

A central goal of DS research is to understand which of the genes on Hsa21, when present in three copies, lead to each of the different DS-associated phenotypes, and to elucidate how increased expression leads to the molecular, cellular and physiological changes underlying DS pathology. Two distinct approaches are being taken to address these issues. First, genomic association studies, such as that recently published by Lyle et al ( 18 )., may point to genes that play an important role in pathology. Secondly, a number of animal models of Hsa21 trisomy have been generated. Recent advances in chromosome engineering have led to the establishment of mice trisomic for different sets of mouse genes syntenic to Hsa21, and a mouse strain, Tc(Hsa21)1TybEmcf (Tc1), carrying most of Hsa21, as a freely segregating chromosome (Fig.  1 ) ( 19 – 27 ). These strains are being used both to map dosage-sensitive genes on Hsa21 and to understand pathological mechanisms. Here, we review recent advances in the understanding of DS-associated phenotypes and the development of therapeutic strategies to treat them.

Development

Trisomy of Hsa21 has a significant impact on the development of many tissues, most notably the heart and the brain. A recent paper has suggested that trisomy of the Hsa21 genes, dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1A ( DYRK1A ) and regulator of calcineurin 1 ( RCAN1 ), may have an impact on the development of multiple tissues ( 28 ). DYRK1A is a priming kinase that facilitates the further phosphorylation of numerous proteins by other kinases (Fig.  2 ) ( 29 – 38 ). It is up-regulated in a number of tissues from people with DS ( 39 , 40 ). RCAN1 is a regulator of the protein phosphatase calcineurin ( 41 ). Crabtree and colleagues hypothesized that trisomy of these two genes may act synergistically to alter signalling via the NFAT family of transcription factors ( 28 ). In an independent study, increased DYRK1A gene dosage was shown to decrease the expression level of RE1-silencing transcription factor ( REST ) ( 42 ). As REST is required both to maintain pluripotency and to facilitate neuronal differentiation, a perturbation in REST expression may alter the development of many cell types. Indeed, over-expression of DYRK1A in some animal models is associated with a number of phenotypes, including heart defects and abnormal learning and memory ( 28 , 33 , 43 – 45 ). However, not all animal models that over-express DYRK1A exhibit these defects, suggesting that polymorphisms or differences in the expression of other genes influence the outcome of DYRK1A trisomy ( 24 ).

Phosphorylation targets of DYRK1A. The Hsa21-encoded kinase DYRK1A has been shown to phosphorylate a multitude of targets, which have been implicated in a number of biological processes and DS-associated phenotypes, including endocytosis and AD.

Trisomy of Hsa21 is associated with a reduction in brain volume, the size of the hippocampus and cerebellum being particularly affected ( 46 – 49 ). A similar phenotype is also observed in the Ts65Dn model ( 50 ). Recent studies have started to elucidate the developmental mechanisms underlying these important phenotypes. Trisomic granule cell precursors from the cerebellum have a reduced mitogenic response to the morphogen sonic hedgehog ( 51 ). This was shown to underlie the reduced number of cerebellar granular cells observed in the Ts65Dn mouse model of DS. Hypocellularity in the hippocampus also has a developmental origin ( 52 , 53 ). Abnormalities in cell-cycle length, apoptosis and neocortical neurogenesis have been shown to contribute to this phenotype ( 53 – 55 ). The reduced level of neurogenesis in Ts65Dn adult hippocampus can be ameliorated by treatment with the anti-depressant fluoxetine, which is a serotonin reuptake inhibitor ( 56 ). Fluoxetine may promote neurogenesis via a number of potential mechanisms, including a direct effect on serotonin levels or via an indirect effect on behaviour. Whether this drug has similar effect during embryonic development has yet to be determined.

Ts65Dn pups exhibit a delay in attaining several developmental milestones, such as forelimb grip and the righting reflex, mimicking the developmental delay observed in babies with DS ( 57 ). A recent report has demonstrated that treatment of Ts65Dn embryos with two neuroprotective peptides reduced the delay in achieving a number of sensory and motor developmental milestones during early post-natal development ( 58 ).

People with DS exhibit craniofacial dysmorphology, including a mandible of reduced size. This phenotype is also observed in the Ts65Dn and Tc1 models ( 26 , 59 ). In the Ts65Dn model, craniofacial dysmorphology is present from early post-natal development and may be related to specific changes in bone development ( 60 , 61 ). The small mandible in people with DS may be caused by migration and proliferation defects in mandible precursor (neural crest) cells in the developing embryo, related to an altered response to sonic hedgehog ( 62 ).

Learning and memory

All people with DS have a mild-to-moderate learning disability. Over-expression of a number of Hsa21 genes, including DYRK1A, synaptojanin 1 and single-minded homologue 2 (SIM2), results in learning and memory defects in mouse models, suggesting that trisomy of these genes may contribute to learning disability in people with DS ( 43 , 45 , 63 , 64 ). In addition, trisomy of neuronal channel proteins, such as G-protein-coupled inward-rectifying potassium channel subunit 2 ( GIRK2 ), may also influence learning in people with DS ( 65 – 67 ). Recent work has demonstrated that trisomy of a segment of mouse chromosome 16 ( Mmu16 ) containing 33 genes including DYRK1A , GIRK2 and SIM2 was necessary, but not sufficient for the hippocampal-based learning deficits in the Ts65Dn mouse model ( 68 ). These data indicate that trisomy of multiple Hsa21 genes is required for the deficits in learning associated with DS. Moreover, Hsa21 trisomy may independently impact on multiple learning pathways.

Recent work on the Tc1 transchromosomic mouse model of DS has examined in detail the learning pathways affected by trisomy of Hsa21 ( 26 , 69 ). The Tc1 transchromosomic model exhibits abnormalities in short-term but not in long-term hippocampal-dependent learning. The learning deficits are correlated with specific abnormalities in long-term potentiation (LTP) in the dentate gyrus of the hippocampus. LTP is an electrophysiological process proposed to be the cellular basis of learning and memory ( 70 ). These data provide insight into which learning mechanisms may be affected by Hsa21 trisomy and can be used to further understand their genetic cause. Structural abnormalities may contribute to these deficits in learning and memory. Indeed, a correlation between specific synaptic abnormalities in the hippocampus of the Ts(16C-tel)1Cje (Ts1Cje) mouse and a defect in LTP has been reported ( 71 ). Moreover, a recent paper has demonstrated an alteration in the amounts of a number of synaptic components in the hippocampus of the Ts65Dn mouse ( 72 ).

Alzheimer's disease

People with DS have a greatly increased risk of early-onset Alzheimer's disease (AD). By the age of 60, between 50 and 70% of the people with DS develop dementia ( 73 – 77 ). The known AD risk factor amyloid precursor protein ( APP ) is encoded on Hsa21. Trisomy of APP is likely to make a significant contribution to the increased frequency of dementia in people with DS. Indeed, triplication of a short segment of Hsa21 that includes APP in people without DS has been recently shown to be associated with early-onset AD. A number of features of neurodegeneration have been observed in mouse models of DS ( 78 – 86 ). Loss of basal forebrain cholinergic neurons (BFCNs) occurs early in AD and also is observed in the Ts65Dn mouse model ( 87 ). Degeneration of BFCNs in Ts65Dn mice is dependent on trisomy of APP and is mediated by the effect of increased APP expression of retrograde axonal transport ( 83 ).

Hsa21 genes other than APP may also contribute to the early onset of AD in people with DS ( 33 , 34 , 40 , 88 – 97 ). Indeed, the Ts1Cje mouse model, which is not trisomic for APP , exhibits tau hyperphosphorylation, an early sign of AD ( 98 ). Recent evidence suggests that trisomy of DYRK1A may contribute to the development of AD in people with DS. DYRK1A can phosphorylate Tau at a key priming site that permits its hyperphosphorylation ( 33 , 36 , 40 , 95 ). DYRK1A may also influence the alternative splicing of Tau and the phosphorylation of APP ( 34 , 99 ). A reduction in the level of protein phosphatase 2A and a decrease in the activity of α-secretase in the brains of people with DS have also been reported, both of which may contribute to AD in this population ( 94 , 100 ). Further studies are required to determine the identity of the trisomic genes that contribute to these phenotypes.

Heart defects

Trisomy of Hsa21 is associated with a number of congenital heart defects, the most common being AVSD that occurs in ∼20% of the people with DS ( 101 ). Mutations in the non-Hsa21 CRELD1 gene may contribute to the development of AVSD in DS ( 102 ). CRELD1 has also been linked to AVSDs by mapping the deletion breakpoints, on chromosome 3, in people with 3p-syndrome. Further studies are required to determine the identity of other genes that are important for heart development in people with DS. A number of Hsa21 trisomy mouse models exhibit heart defects similar to those observed in DS, suggesting that trisomy of one or more of the approximately 100 genes common to these models influences development of the heart ( 22 , 26 , 103 , 104 ).

Leukaemia and cancer

DS increases the risk of developing AMKL and acute lymphoblastic leukaemia (ALL). Approximately 10% of the DS newborns present with a transient myeloproliferative disorder (TMD), characterized by a clonal population of megakaryoblasts in the blood. This transient disease usually spontaneously resolves; however, 10–20% of the DS patients with TMD develop AMKL before 4 years of age (reviewed in 105 ). The development of TMD requires both trisomy 21 and mutations in the transcription factor GATA1 ( 106 , 107 ). It is likely that further mutations are required for TMD to develop into AMKL. The GATA1 mutations found in TMD and AMKL always have the same effect, causing translation to initiate at the second ATG of the coding region, leading to the production of a shorter protein, termed GATA1s. Trisomy of Hsa21 on its own, even in the absence of GATA1s, leads to an expansion of the megakaryocyte-erythroid progenitor population in fetal livers from human DS abortuses ( 108 , 109 ). These data suggest that trisomy of Hsa21 perturbs hematopoiesis, making megakaryocyte-erythroid progenitors susceptible to the effects of GATA1s, thereby promoting development of TMD. Several groups have reported the presence of mutations in Janus Kinase 3 ( JAK3 ) in a small proportion of TMD/AMKL patients ( 110 – 115 ). It was suggested that JAK3 inhibitors could be used as a therapy ( 111 , 114 ). However, both loss- and gain-of-function mutations have been found, so this may not be a viable treatment. Stem cell factor/KIT signalling has recently been demonstrated to stimulate TMD blast cell proliferation, and inhibitors of this pathway may be a treatment for severe TMD ( 116 ).

Attempts have been made to model these disorders in mice with a view to establishing which genes on Hsa21 need to be present in three copies in order to induce disease. A study of the Ts65Dn mouse model showed that it developed a late-onset myeloproliferative disorder, but did not develop leukaemia ( 117 ). It may be that the Ts65Dn model is not trisomic for the relevant dosage-sensitive genes required for the development of AMKL or that the expression of a mutant form of GATA1 will be required to increase the frequency of leukaemogenesis in this mouse model of DS.

The genetic events involved in DS-ALL are less well understood than those in DS-AMKL. A number of studies have reported DS-ALL cases with chromosomal abnormalities, gain-of-function mutations in JAK2 and submicroscopic deletions of genes including ETV6 , CDKN2A and PAX5 ( 118 – 121 ).

Although the incidence of leukaemia and cancer of the testis are increased in DS, the risk of developing most solid tumours is reduced ( 122 , 123 ). Crossing mouse models of DS with mice heterozygous for the Apc min mutation reduced the number of tumours, which would normally accumulate in this model of colon cancer ( 124 ). Protection against the development of tumours required three copies of the Hsa21 ‘proto-oncogene’ Ets2 , suggesting that in this context, Ets2 may be acting as a tumour suppressor ( 124 ).

Hypertension

People with DS have been reported to have a reduced incidence of hypertension ( 125 , 126 ). Trisomy of the Hsa21 microRNA hsa-miR-155 may contribute to this ( 12 ). Hsa-miR-155 is proposed to specifically target one allele of the type-1 angiotensin II receptor ( AGTR1 ) gene, resulting in its under-expression, which may contribute to a reduced risk of hypertension. Further studies are required to validate this hypothesis and determine whether other genes may also protect people with DS against hypertension.

Recent interest in therapy for people with DS has focused on pharmacological treatment to enhance cognition. A number of compounds have been shown to improve learning in the Ts65Dn mouse model. Chronic treatment with picrotoxin or pentylenetetrazole improved hippocampal-based learning and LTP deficits in Ts65Dn mice, even after treatment had ceased ( 127 ). These compounds reduce gamma-aminobutyric acid-mediated inhibition in the hippocampus and are proposed to improve cognition by releasing normal learning from excess inhibition. Learning in Ts65Dn mice is also improved by the non-competitive N-methyl-D-aspartic acid receptor (NMDAR) antagonist, memantine ( 128 ). Memantine partially inhibits the opening of the NMDAR and is proposed to counter the effect of trisomy of RCAN1 on the function of the receptor. Further studies and clinical trials are required to further investigate the potential of these drugs to improve cognition in people who have DS.

To develop new therapeutic targets, it is necessary to determine the identity of genes that contribute to DS phenotypes. This requires a precise and standardized definition of phenotype. Ideally, these measurements should be formulated into a standardized protocol that can be applied at multiple centres, to permit sufficiently large numbers of samples for meaningful analysis to be collected. This can be facilitated by a carefully designed and curated biobank of detailed phenotypic data alongside DNA and tissue samples from participating individuals. These collections can then be used for both candidate gene and genome-wide analyses, by different investigators, permitting the identification of both dosage-sensitive trisomic Hsa21 and non-Hsa21 genes that contribute to DS phenotypes. Pooling of large data sets has led to recent important findings in the study of schizophrenia, diabetes and obesity, illustrating the importance of large-scale collaboration ( 129 – 132 ). The careful collection of additional patient data will add much to our current understanding of DS.

As recent progress demonstrates, mouse models can be used in parallel with data collected from people with DS to test genetic associations, to explore biological mechanisms and to trial therapies. In addition to the long-standing Ts65Dn and Ts1Cje models, the newly developed mouse strains such as Tc1, Dp1Yu and Ts1Rhr have generated a range of models with distinct sets of trisomic genes (Fig.  1 ) ( 19 – 27 ). Furthermore, the crossing of these strains with mice-bearing deletions of chromosomal segments syntenic to Hsa21, such as Ms1Yah and Ms1Rhr (Fig.  1 ), will allow systematic mapping and eventually identification of the dosage-sensitive genes causing DS-associated pathology.

DS was once thought to be an intractable condition because of the genetic complexity underlying it. Here, we have described recently reported breakthroughs in the understanding of Hsa21 trisomy, illustrating that research efforts in this field are making significant strides to understand and to develop treatments for the debilitating aspects of the syndrome. Many issues vital to the health and well-being of people with DS remain to be studied, making this an important and exciting time for Hsa21 trisomy research.

V.L.J.T. and K.A.A. are funded by the UK Medical Research Council, the EU, the Leukaemia Research Fund and the Wellcome Trust; F.K.W. and E.M.C.F. are funded by the UK Medical Research Council, the Wellcome Trust and the Fidelity Foundation.

We thank Roger Reeves, Dalia Kasperaviciute, Olivia Sheppard and Matilda Haas for advice on the manuscript and we thank Ray Young for help with preparation of the figures. We apologize to the many authors whose work we were unable to cite owing to space limitations.

Conflict of Interest statement . None declared.

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• down syndrome
• chromosomes
• chromosomes, human, pair 21
• engineering
• mental processes
• animal model
• learning disabilities
• cognitive ability
• childhood leukemia
• alzheimer disease, early onset

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• Published: 23 March 2022

Conducting clinical trials in persons with Down syndrome: summary from the NIH INCLUDE Down syndrome clinical trials readiness working group

• Nicole T. Baumer 1 ,
• Mara L. Becker 2 ,
• George T. Capone 3 ,
• Kathleen Egan 4 ,
• Juan Fortea 5 , 6 , 7 ,
• Benjamin L. Handen 8 ,
• Elizabeth Head 9 ,
• James E. Hendrix 10 ,
• Ruth Y. Litovsky 11 , 12 ,
• Andre Strydom 13 , 14 ,
• Ignacio E. Tapia 15 &
• Michael S. Rafii   ORCID: orcid.org/0000-0003-2640-2094 16  

Journal of Neurodevelopmental Disorders volume  14 , Article number:  22 ( 2022 ) Cite this article

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The recent National Institute of Health (NIH) INCLUDE (INvestigation of Co-occurring conditions across the Lifespan to Understand Down syndromE) initiative has bolstered capacity for the current increase in clinical trials involving individuals with Down syndrome (DS). This new NIH funding mechanism offers new opportunities to expand and develop novel approaches in engaging and effectively enrolling a broader representation of clinical trials participants addressing current medical issues faced by individuals with DS. To address this opportunity, the NIH assembled leading clinicians, scientists, and representatives of advocacy groups to review existing methods and to identify those areas where new approaches are needed to engage and prepare DS populations for participation in clinical trial research. This paper summarizes the results of the Clinical Trial Readiness Working Group that was part of the INCLUDE Project Workshop: Planning a Virtual Down Syndrome Cohort Across the Lifespan Workshop held virtually September 23 and 24, 2019.

Background/introduction

The INCLUDE (INvestigation of Co-occurring conditions across the Lifespan to Understand Down syndromE) project was launched in June 2018 in support of a Congressional directive in the fiscal year (FY) 2018 Omnibus Appropriations. The directive called for a new trans-NIH research initiative on critical health and quality-of-life needs for individuals with Down syndrome (DS) and resulted from advocacy from the community, NIH commitment, and generous support from Congress. This program is developing a portfolio of scientific opportunities that span the spectrum from basic science to clinical research. Important insights are being gained from INCLUDE studies, and the capacity building (especially training for a cadre of investigators who will advance the field) that the program has accelerated provides confidence that this research trajectory will enhance the lives of people with DS.

The NIH INCLUDE project hosted a workshop titled “Planning a Virtual Down Syndrome Cohort Across the Lifespan Workshop.” Groups interacted via teleconferences and email during a 3-month preparation period. A 2-day face-to-face meeting was held virtually, September 23 and 24, 2019, at which all working groups presented their findings and participated in additional discussion and refinement of the initial work. At the workshop, specialists, including clinicians, researchers, advocates (parents and individuals with DS), as well as data scientists and biostatisticians, were brought together to discuss the creation of a virtual DS cohort across the lifespan. A final overview of the status of best practices for engaging and conducting clinical trials in the DS population was developed by the Clinical Trial Readiness Working group and is presented in the following sections. The focus of this paper is to outline current challenges and opportunities in clinical trial research in people with DS and to present recommendations for future work in this area.

Current state of clinical trials in the Down syndrome population

Ongoing clinical trials with individuals with DS address a wide range of conditions and issues, such as Alzheimer’s disease (AD) dementia, cardiac disease, metabolic disorders and obesity, autoimmune disorders, obstructive sleep apnea (OSA), leukemia, behavioral, and mental health issues. Advances in medical care have improved overall health and extended the life span of individuals with DS. Current research is focused on development, cognition, with the goal of maximizing functional outcomes and improving their quality of life.

Great strides have been made in observational and behavioral research in DS, with thorough characterization of development and cognition [ 1 , 2 ], as well as development of new tools to detect AD-related cognitive decline in adulthood [ 3 , 4 ]. Working groups have also evaluated potential outcome measures that can be used in clinical trials in the areas of cognition and behavior [ 5 ]. However, despite these advances, clinical trial research, particularly that focused on cognition, has been slow to progress and poses unique challenges [ 6 , 7 ]. Several issues have impacted the success of clinical trials in DS, and more broadly within neurodevelopmental disabilities (NDDs). These include barriers that individuals with DS and their families experience, ethical and logistical barriers that researchers face, and challenges with clinical trial research design and interpretation.

Challenges and barriers for conducting clinical trials

The number of families and individuals with DS who participate in research and clinical trials is not sufficient to obtain valid and reliable results. NIH has created a DS Registry and while the numbers have increased over the past years, there is still a need for greater involvement of a larger number of participants.

Barriers faced by families

The biggest barrier is trust in most cases and/or the lack of exposure to the benefits of research. This results from limited community awareness and interest and therefore involvement in research, particularly in racially and ethnically diverse populations. Those who face disadvantage, be it due to factors such as disability, socioeconomic status, and/or ethnic/minority background, have expressed that it can be difficult for them to take part in research activities, and report their views and experiences are less often heard and addressed [ 8 ].

The logistical burden of participating in clinical trials is also cited as a challenge for families of individuals with DS, with families concerned about scheduling burden, family availability, overall time commitment, travel distance, out-of-pocket expenses, and frequency of visits [ 9 ]. These challenges are likely exacerbated in older individuals for whom caregivers are also older, or for individuals who are living in settings outside of the family home. Exploration of parent attitudes reveals that while many parents of individuals with DS generally support pharmacological trials, there are concerns about safety and long-term implications, potentially limiting participation [ 9 , 10 ]. Decisions regarding participation in clinical trials may be dependent on the intervention target, such as medical versus developmental conditions/cognition or high priority symptoms such as communication or behavior [ 9 ]. People with DS may also have difficulty complying with study demands due to motor limitations, impulsivity, and limited attention span, and may require specialized testing administration, and customization.

Ethical and logistical barriers faced by researchers

Challenges with recruitment, retention, consenting/assenting, and logistics, safety, and efficacy have also long impacted clinical trial research in DS and special considerations are needed for success [ 6 , 7 ]. Given the historical context of exploitation, there are issues surrounding the ethical and legal implications for conducting research with individuals with intellectual disability (ID) [ 11 , 12 ]. For example, some researchers may be reluctant to include people with ID in their research for several reasons: they may inappropriately presume inability; they may be concerned about the capacity of the individual to understand risks and benefits and provide consent or assent to participate; or they may consider those with ID to be vulnerable and in need of protection from potential harms of research. While DS researchers may be well trained and experienced, and have comfort in addressing these issues, researchers less familiar with DS or ID, but who study health issues relevant to DS may not be. Choice of participants can also be problematic, as those with more severe impairments who may not be able to comply with study demands may not be well represented by findings originating from study participants with milder impairments who are better able to participate in research.

Challenges specific to clinical trials targeting cognition

There are specific challenges to clinical trials that target cognition, neurodevelopment, and neurodegeneration. These include heterogeneity within the population, interindividual variability, lack of standard endpoints to assess efficacy, placebo effects, reliance on informant-based questionnaires that require the same informant at multiple time points, and complexity in interpretation of findings. Current research most commonly involves those who have mild-moderate ID, and findings may not be generalizable to those with more severe impairment.

Clinical trials in DS have faced similar challenges to clinical trials in other NDDs. For example, in Fragile X, despite great success in understanding genetic and mechanistic causes of cognitive impairments and positive findings in mouse models, human studies of targeted pharmacologic treatments for cognition have not yet shown significant improvement in outcomes, and some pharmaceutical companies have discontinued further drug development [ 13 ]. However, there are many complexities to interpreting the available findings. It may be that studies are too quick to conclude that negative findings in a trial prove that a treatment is ineffective under all conditions or that the presumed underlying pathophysiological mechanisms are not valid [ 14 ]. For example, some treatments may be effective in certain subgroups of the population, at a different time in development, or under different conditions.

Without potential biomarkers of treatment response, human trials need to rely on behavioral outcomes, which reflect combined effects of many different factors such as learning and environment. Additionally, the behavioral outcome measures may not be sensitive enough to treatment effects, or best suited to the population studied or what is most relevant to families and people with DS. Standardized behavioral-based assessments have floor and ceiling effects and direct measurement testing batteries may over- or underestimate participant’s skills because they are not geared to their specific profile. Reliance on informant-based questionnaires is also particularly susceptible to strong placebo effects in NDDs [ 15 ].

Variability in cognition, behavior, language, and adaptive skills is seen in people with DS, and skills in these domains evolve across the lifespan, with environmental influences playing a role in ways that are not well characterized or understood. Furthermore, how medical and mental health conditions that occur at different times over the lifespan further influence neurodevelopment and outcomes.

While a longitudinal lifespan approach would help to answer important clinical questions that address both neurodevelopmental and neurodegenerative aspects of DS, there are many challenges to a lifetime approach as brain development, organization, maturation, and functioning evolve over time, and there may be critical windows for potential treatments to have desired effects. Additionally, pharmacological treatments targeting cognition or learning may need to be paired with structured therapy/teaching paradigms and study impact over longer time periods to adequately assess effectiveness of a drug that has the potential to enhance the learning process.

Clinical trials readiness working group objectives

The Clinical Trial Readiness Working Group was provided with key questions and tasked with developing responses that could serve as a roadmap for efforts going forward in advancing clinical research efforts in DS and increasing participation among persons with DS in future clinical trials. The questions focused on (1) identification of approaches to facilitate recruitment and retention of research participants, including underrepresented groups, (2) cohort preparation for clinical trials with special considerations for clinical trials across the lifespan, and (3) building a pipeline of investigators with DS clinical trial experience. In exploring these questions, several themes emerged and fostered development of the recommendations that follow.

Recruitment and retention: strategies to promote engagement and inclusion

Engagement with individuals with ds, their families/care partners, and community advocacy organizations.

Ensuring that research teams include members from the groups studied has been increasingly recognized as an important aspect of research involving individuals with disabilities [ 7 , 15 ]. The shift from “researching on” to “researching with” has helped investigators understand the types of outcomes that are perceived to be useful within the community and can contribute valuable information to study design and implementation [ 16 ].

The Working Group identified areas of need and suggestions for recruitment and retention of research participants, with particular focus on engaging and involving groups often underrepresented in medical research. Involving individuals with DS and their families at all phases of research and fostering and maintaining research collaborations are necessary to promote engagement and advance clinical research while helping to further the understanding of needs and priorities.

Surveys, focus groups, and consultation and advisory feedback from families and participants can be particularly helpful when developing study questions and designing clinical trials. This can help to ensure understandability and feasibility of study assessments, outcome measures, information and consent materials, and will help researchers understand the relevance of the study question to participants and how they would like information conveyed. Some family members may have professional expertise that aligns with clinical and scientific goals. Investigators should take a community-engaged/community-based participatory research approach (CBPR), in which they collaborate with the community, and incorporate stakeholders’ expertise, values, and priorities in all steps of the research process [ 17 ].

Community engagement and outreach events may enhance outreach and education and can be conducted in person or virtually. Social media, websites, and newsletters from advocacy organizations can be used to advertise studies. Partnering with DS associations and societies (e.g., National Down Syndrome Society (NDSS), Global Down Syndrome Foundation (GDSF), LuMind Foundation, National Down Syndrome Congress (NDSC), Trisomy 21 Research Society (T21RS)), and religious and community groups, government, and advocacy groups will also support this effort. Importantly, an individual and family’s experience in a trial not only impacts retention for that trial but impacts recruitment for future trials. Partnerships can be further strengthened and promoted by engagement in which materials and information about ongoing studies can be disseminated. These efforts can help to promote partnerships, buy-in, and willingness for individuals to be contacted in the future for research opportunities.

Collaboration between researchers, clinicians, stakeholder groups, and advocacy organizations

In addition to strong community engagement, successful recruitment will rely on collaboration among clinicians and researchers, stakeholder groups, and advocacy organizations. Strong relationships with referring clinical programs, and in collaboration with clinicians who have pre-existing relationships with potential participants, will enable research to be considered as an extension of clinical care, with both clinical and research cultures existing synergistically. It is necessary to continue to build a strong network of clinical care centers for people with DS, and for researchers to collaborate closely with clinicians and to collaborate in study recruitment and study conduct, such as for collecting data from the clinic sample. Researchers should engage clinicians as partners and respect their involvement (e.g., the face of the study, collaborators on publications).

Partnerships between academic researchers and industry are needed to conduct large scale randomized, placebo-controlled clinical trials. Collaborations with researchers who focus on other areas of developmental disabilities may be useful to broaden the scope of endpoints. Continued collaborations with NIH and the Down Syndrome Medical Interest Group (DSMIG-USA), collaborations with researchers and clinicians, basic scientists, and clinical researchers are needed to further this effort.

Engagement of underrepresented groups

Engagement and involvement of minority groups who are underrepresented in biomedical research is a particular challenge. It is necessary to incorporate strategies that address cultural and language barriers, such as adapting information, providing translations for written documents and interpreters for oral communications, and targeting recruitment. It will be necessary to identify strategies to gain information about the ages, ethnicities, and races of people with DS in research catchment areas and clinical research sites and to work closely with the community to engage participants. Recruiting people from various backgrounds and minority groups can also be enhanced by inclusion of people on the research team that captures this diversity.

Providing accessible information

A careful and thorough process of communication is needed when conducting research in individuals with DS. Use of accessible information and repeated opportunities to communicate information and check for understanding are needed. Novel ways to address informed consent, such as through picture-based consents and electronic consenting platforms (eConsenting), are needed. For example, the U.S. Food and Drug Administration has guidance on use of electronic consents [ 18 ]. Involvement of individuals with DS and their families in reviewing consent materials is especially important. Individuals with DS may be inclined to give socially desired answers, so checking for understanding and use of visually accessible information is needed.

Timely and accurate dissemination of important findings, including safety information and results, is imperative. New and creative ways to acknowledge participation in research and to share and distribute study results are crucial. Information should be shared in formats that are appropriate to the audience, such as through a newsletter or infographic, rather than a journal article. For example, T21 RS COVID-19 infographic summaries, vetted through stakeholders and advocacy groups, have proved to be a successful method for dissemination of key research findings [ 19 ]. Providing a platform for patients and research participants to share their experience in research with others may also be a valuable tool for all stakeholders.

Reducing study burden

Trial burden may be decreased by using telemedicine and home visits, or by coordinating research with clinic visits or on nights or weekends, so as not to interfere with school, work and other activities and appointments. Budgets should reflect the additional cost required to bring in research staff on off-hours. It is also important to ensure that families, participants and care partners are appropriately supported to attend visits (e.g., travel arrangements and reimbursement, compensation for use of care hours, flexibility in timing of visits, adequate breaks during study visits.) Travel for adult participants, especially, can be a barrier to participation, and travel expenses should be included in the budget. Group travel for individuals with Down syndrome living together in a group home can save money and be enriching for participants. In addition, remote visits, such as via telemedicine, could also reduce travel burden for participants and expand research catchment areas. Direct to patient trials in which study treatments and procedures are delivered in the participant’s home could also be considered to optimize recruitment and minimize burden to patients and families [ 19 ].

Data collection in research areas of high interest (e.g., sleep, behavior, cognition, mental health) are extremely labor- and time-intensive to conduct. Development of select web-based, interactive assessment tools (point-click-scroll) will be helpful to partially replace the need for in-person visits. Some studies are also completed entirely online, such as the Alzheimer’s Prevention Trials web-based research study [ 20 ]. Efforts are needed to begin to validate these tools and compare to gold-standard assessments, and also to collect data longitudinally to determine test-retest reliability. Feasibility trials/pilot studies are likely to be needed before larger scale trials are conducted.

Legal and ethical considerations

Autonomy and self-determination must be respected and balanced with the responsibility to protect vulnerable individuals from potential risks of participation in research studies, thus the informed consent process, in particular, demands careful planning.

Given the ID associated with DS, as well as potential emotional/behavioral conditions that influence decisions, individuals with DS must be supported in research decision-making. In many cases, and depending on the legal framework, a surrogate or proxy decision maker is involved, and a legally authorized representative makes decisions about participation. Many individuals are comfortable receiving assistance from trusted family and friends to help them with decisions. Even for individuals who cannot provide legal consent, they may be able to express their thoughts and feelings about participating and exercise some choice. Assent—or willingness of the prospective participant to go along with or not object to the study—is essential, even when there is a surrogate decision-maker.

Special consideration is also needed for recruitment/consenting of aging adults with DS or adults living in group homes who may lack a legally authorized representative or family informant. The legally authorized representatives of adults with DS often change over time, for example, from an aging parent to a sibling or professional caregiver. Each state or country has different regulations around consent for individuals with disabilities. This must be determined in advance to inform clinical trial development, with particular consideration of multisite/multiregional studies, and local/state regulations must be taken into consideration.

Cohort development across the lifespan

Cohort development across the lifespan is critical for readiness for future clinical trials. These trial ready cohorts might accelerate research for several clinical needs (e.g., AD and OSA), thus reducing the costs of performing different clinical interventions. Further development of reliable and valid clinical outcome measures across the lifespan and across a wide range of developmental abilities are needed. Longitudinal studies are needed to better understand the natural history of DS and its associated conditions, to identify DS-related norms, to help identify subgroups with characteristics, to understand what childhood factors may predispose to risk or resilience, and who may be good candidates for preventative interventions.

Many medical issues for adults with DS such as obesity and sleep apnea begin in childhood and childhood antecedents may play an important role in how these, and other adult-onset conditions, evolve. For example, AD, which is one of the most prevalent and challenging conditions for adults with DS, has genetic but also likely environmental origins early in childhood [ 21 ]. Some research in the general population has shown associations between AD and increased exposure to adverse childhood experiences (including living in custody and difficult experiences with teachers) [ 22 , 23 ]. In addition to research trials in older adults, longitudinal studies in DS will be needed in DS to understand early risk factors and the potential impact of childhood experiences. Additionally, the association between OSA in adults with AD is currently under investigation in the general population [ 24 ]. With high rates of OSA in people of all ages with DS, it will be important to understand whether OSA in childhood might impact later risk of AD. Similarly, research in typically developing children has shown that persistent sleep problems through childhood are associated with worse behavioral outcomes and quality of life. A longitudinal study in individuals with DS might be able to provide important insight into the association between sleep and health outcomes across the lifespan [ 25 ]. Furthermore, there are conditions that arise specifically in childhood, for example DS-associated arthritis that can affect long-term physical outcomes. DS-associated arthritis is under-recognized, has a more severe phenotype, and is difficult to treat. It can result in disruptions in motor development, unpredictable medication toxicity and significant long-term physical disability [ 26 ].

Ongoing work to accelerate the development, evaluation, and validation of new trial-enabling standardized outcome measures for use over the lifespan is also needed. Many measures currently used in neurotypical children and adults cannot be used in those with DS. Cognitive measures are needed that are normed for individuals with DS and age appropriate, which are sensitive to bidirectional change (i.e., can detect developmental growth and skill acquisition as well as decline), and that can be used in individuals with a wide range of abilities, including those with more severe ID [ 5 ].

While longitudinal lifespan studies are logistically challenging, through close collaboration among the DS-community and advocacy organizations, specialized pediatric and adult clinical DS programs, and researchers, large registries and clinical databases of well-characterized cohorts can be created and shared. NIH-funded Data Coordinating Centers [ 27 ] can lead these efforts by serving as a platform for linking investigators for collaborative research. Additionally, with opportunities for clinical research throughout the lifespan, more touchpoints and ongoing engagement can be fostered for future recruitment into clinical trials. Exposure to research results and sharing the successes in a case study can help build trust. Also, most publications are usually scientific and do not reach the target population. The recommendation is to publish for the target population on their websites and share these in DS conferences to convey results and findings to the population.

The timing of interventions will be critical to consider. In younger children, developmental change will be expected in the absence of intervention, and in older individuals, there may be points at which aberrant neurodevelopment or the later neurodegenerative cascade, are too far underway such that neurobiological consequences are irreversible and functioning cannot be altered. Additionally, specific brain areas impacted in DS mature at different rates and manifestations of their disrupted development change across the lifespan, suggesting that some pharmacological targets may be most effective at different time points in development. For these reasons, targeting younger individuals for treatment and prevention trials, in addition to older adults, may be an additional important approach.

Clarity is needed on a regulatory pathway for new drugs for DS, as the typical progression of drug development that is initiated in neurotypical adults, then children, may be problematic. It is not clear that demonstration of safety in a neurotypical population would predict safety in DS. In addition, individuals with DS are at increased risk for numerous co-occurring conditions that require chronic medications and very little is understood about drug biotransformation in DS, despite observed differences in drug response and toxicity [ 28 , 29 , 30 ]. Dedicated pharmacodynamic and pharmacokinetic studies, such as those conducted through the Pediatrics Trials Network—currently investigating metabolism of Guanfacine in Down syndrome—are needed more broadly in DS to determine drug disposition and response relationships, and to establish safety and dosing recommendations across the lifespan. Additionally, training and expertise are needed for identifying and managing potential adverse events, particularly when participant reporting of side effects and problems may not be straightforward.

Coordinated efforts across many sites will be needed to build large cohorts, and leverage existing infrastructure, including Alzheimer's Disease Research Centers (ADRCs), Centers for Excellence in Developmental Disabilities (CEDDs), Intellectual and Developmental Disability Research Centers (IDDRCs) and others. Harmonization of test batteries across studies and across age groups is desired so that results can be compared and aggregated across studies. Several strategies can help with cohort development, including continued support of DSConnect and similar efforts to build a registry of interested participants, continued work to prepare and maintain lists and coordination of existing cohorts through the Data Coordinating Centers, and ensuring that new research study design is tailored and compatible with existing cohorts. This involves ongoing work to determine a minimum set of core data elements and informative measures, and to create standard operating procedures to facilitate systematic collection of biological and standardized and consistent behavioral data across studies and sites.

Building an investigator pipeline in Down syndrome research

Coincident with bolstering clinical trial participation by members of the DS community, there is a critical need to have clinical research sites trained and resourced to conduct such studies. The Working Group offered several recommendations to support this effort. The INCLUDE infrastructure can be used to bring in early stage as well as established investigators into the DS research space by capitalizing on existing training mechanisms, such as NIH Career Development and Training pathways (e.g., K23, T32 training awards).

Interest in DS research can be expanded and fostered by engaging clinicians, researchers, and trainees including those who are not focused solely or primarily on DS or even ID and providing training and mentorship. To encourage DS clinicians to participate, it will be necessary to offer training bootcamps to provide skills in clinical trial design, implementation, and funding, as well as ongoing mentoring opportunities.

In order to encourage other researchers to include people with DS or other intellectual and developmental disabilities in their research, it will be necessary to provide training on how to interact with and include people with DS.

Training opportunities can be built into NIH clinical trials infrastructure such as the Pediatric Trials Network (PTN) and Alzheimer’s Clinical Trials Consortium (ACTC). For example, ACTC launched the IMPACT AD training course in 2020. Lectures are given by national leaders in Alzheimer’s Disease and Related Dementias (ADRD) trials, and attendees have the opportunity to work closely with the field’s top investigators in small group workshops. Groups such as the ADRC can be encouraged to recruit and help train investigators interested in focusing on DS. There is now a DS module developed by the National Alzheimer’s Coordinating Center (NACC) that can be implemented at all ADRCs. It will be important to develop international links and collaborative networks via organizations such as the Alzheimer’s Association International Society to Advance Alzheimer’s Research and Treatment (ISTAART) and T21RS to capitalize on global expertise. All NIH funded ADRCs also now include a Research Education Component that could be coordinated to provide training modules on the importance of research in people with DS and Alzheimer disease.

The PTN also launched a PTN Down Syndrome 2020 Virtual meeting to introduce to the larger network and interested collaborators the therapeutic challenges faced by children with DS; opinions of community advocates, individuals, and parent/family on engaging in current and future research; lessons learned from current efforts to enroll patients with Down syndrome into an active PTN study; and input on a prospective randomize clinical trial protocol in development.

Existing IDDRCs can also be leveraged to fund postdocs and/or PhD positions in their labs to draw students from other fields into the DS space. This can be accomplished by offering CME activities and presenting workshops/symposia at national meetings focused on DS/ID [e.g., DSMIG-USA, DSMIG-UK, Child Neurology Society (CNS), American Academy of Neurology (AAN), AAIDD-Gatlinburg, and American Academy of Developmental Medicine and Dentistry (AADMD)] or with stakeholders not focused solely or primarily on DS or even IDD (e.g., AMA, APA, AAIC.) Finding ways to support student/young investigator attendance at these meetings will also be important.

Discussion/key points

Advancing research in DS will require ambitious and collaborative efforts that reach across the lifespan and include researchers, clinicians, individuals with DS and their families, advocacy groups, and industry. The Clinical Trial Readiness Working Group has identified many challenges and opportunities for these efforts and has suggested approaches in developing some of the infrastructure and methods needed to conduct clinical trials successfully in people with DS.

Specifically, the Working Group highlighted the importance of the following:

Stakeholder engagement from the inception of any research project.

Ethical, accessible (culturally and cognitively appropriate) recruitment materials, ensure collection of assent as part of the consenting process if a legal guardian is providing consent, study materials, and dissemination of results available in different languages.

A lifespan approach from time of diagnosis (including prenatal diagnosis) to death both to evaluate childhood antecedents of adult disease or decline and to evaluate effects of interventions.

Development of appropriate tools to assess outcomes in health, quality of life, cognitive functioning and behavioral/mental health that can be used across institutions and age ranges.

Workforce development of a pipeline of researchers and clinicians to collaborate in ongoing research efforts.

Conclusions

As we develop more advanced infrastructure to translate research towards clinical benefit for individuals with DS, it will be critical to continue the efforts described by the Working group to achieve the best possible outcomes and ensure that important research opportunities are accessibility for all.

Availability of data and materials

Not applicable.

Abbreviations

National Institute of Health INvestigation of Co-occurring conditions across the Lifespan to Understand Down syndromE

• Down syndrome

Neurodevelopmental disabilities

• Intellectual disability

National Down Syndrome Society

Global Down Syndrome Foundation

National Down Syndrome Congress

Trisomy 21 Research Society

Down Syndrome Medical Interest Group-USA

Obstructive Sleep Apnea

Alzheimer's Disease Research Centers

Centers for Excellence in Developmental Disabilities

Intellectual and Developmental Disability Research Centers

Pediatric Trials Network

Alzheimer’s Clinical Trials Consortium

Alzheimer’s Disease and Related Dementias

Institute on Methods and Protocols for Advancement of Clinical Trials in ADRD

National Alzheimer’s Coordinating Center

International Society to Advance Alzheimer’s Research and Treatment

Child Neurology Society

American Academy of Neurology

American Association on Intellectual and Developmental Disabilities

American Academy of Developmental Medicine and Dentistry

American Medical Association

American Psychological Association

Alzheimer’s Association International Conference

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Acknowledgements

We would like to thank Dr. Kelly King and Dr. Melissa Parisi of NIH for their collaboration on this manuscript.

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All authors have reviewed this manuscript to report. NB and MSR participated in the working group that served as the basis for this manuscript and also led the writing of the manuscript. MLB, GTC, KE, JF, BLH, EH, JEH, RYL, AS, and IET participated in the working group and provided comments and edits to the final manuscript. The authors read and approved the final manuscript.

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Baumer, N.T., Becker, M.L., Capone, G.T. et al. Conducting clinical trials in persons with Down syndrome: summary from the NIH INCLUDE Down syndrome clinical trials readiness working group. J Neurodevelop Disord 14 , 22 (2022). https://doi.org/10.1186/s11689-022-09435-z

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Published : 23 March 2022

DOI : https://doi.org/10.1186/s11689-022-09435-z

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Several Down syndrome features may be linked to a hyperactive antiviral immune response – new research

Professor of Pharmacology, University of Colorado Anschutz Medical Campus

Disclosure statement

Joaquin Espinosa receives funding from the National Institutes of Health, the Global Down Syndrome Foundation, and the Anna and John J. Sie Foundation. Dr. Espinosa has provided consulting services to Elli Lily and Co. and Gilead Sciences Inc. and currently serves in the advisory board of Perha Pharmaceuticals.

University of Colorado Anschutz Medical Campus provides funding as a member of The Conversation US.

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People with Down syndrome , or trisomy 21, a genetic condition caused by an extra copy of human chromosome 21, experienced a remarkable increase in life expectancy during the 20th century. In the early 1900s, less than 20% of newborns with Down syndrome survived past age 5 . In the U.S. today, more than 90% of babies with this condition live past age 10 and have a life expectancy of nearly 60 years . These increases were likely fueled by greater inclusion in general society, the discontinuation of institutionalization in psychiatric facilities and better medical care.

Despite these advances, people with trisomy 21 experience an increased risk of many co-occurring conditions , such as congenital heart defects, autoimmune conditions, autism spectrum disorders and Alzheimer’s disease. On the other hand, people with Down syndrome tend to have lower levels of hypertension and certain types of cancers .

Understanding how an extra chromosome 21 causes these risks and resiliencies could advance collective understanding of major medical conditions that also affect the general population. For example, the increased risk of Alzheimer’s disease among adults with Down syndrome can be explained in part by the presence of a gene on chromosome 21 that leads to excess production of the beta-amyloid proteins and plaques characteristic of Alzheimer’s.

In our newly published research, my research team and I found that genes involved in controlling the immune system are critical to the development of multiple hallmarks of Down syndrome. Our findings contribute to a growing body of research on the immune system’s important role in the appearance and severity of some of the negative health effects of trisomy 21, supporting the idea that restoring immune balance could help improve the quality of life of people with the condition.

When too much of a good thing is bad

The genes we identified, which encode what are called interferon receptors , are an important part of the immune system’s antiviral defense. These genes enable our cells to recognize a set of proteins called interferons, which virus-infected cells produce to alert the yet uninfected cells around them about the presence of a virus during an infection.

While interferons do trigger a beneficial immune response against viral infections, chronic interferon hyperactivity could have detrimental effects. Too much interferon signaling is known to be harmful in medical conditions such as systemic lupus erythematosus , a group of genetic disorders known as interferonopathies and severe COVID-19 .

Notably, four of the six human interferon receptor genes are located on chromosome 21 . Most people have only two copies of each chromosome and so would have only two copies of these genes. Because people with Down syndrome have three copies of chromosome 21, they also have three copies of the interferon receptor genes on it. This contributes to the overproduction of interferon receptors seen in those with Down syndrome.

Our team wanted to know whether this extra copy of interferon receptor genes , compared with the roughly 200 other genes located on chromosome 21, contribute to features of Down syndrome. To do this, we used a mouse model of Down syndrome. In this mouse model, a large region of its genome that is equivalent to a large portion of human chromosome 21 is triplicated to reproduce many features of Down syndrome.

Using CRISPR gene editing technology, we reduced the number of interferon receptor genes from three to the typical two, leaving all other triplicated genes intact. We found that correcting the number of interferon receptor genes significantly reduced abnormal gene expression patterns across multiple tissue types, both during embryonic development and in adult mice. These mice also had more regulated immune responses, normal heart development, reduced developmental delays, improved performance on memory and learning tasks and even a more typical skull and facial morphology.

Overall, our findings suggest that the tripling of interferon receptor genes may cause a number of key traits of Down syndrome.

Therapeutic implications and future directions

Our research indicates that many, though not all, aspects of Down syndrome may be associated with hyperactivity of the immune system’s interferon response. It also supports the possibility of using drugs that attenuate this response to treat some of the negative health effects of trisomy 21.

Our team is currently leading two clinical trials to test the safety and efficacy of one such drug, tofacitinib (Xeljanz) . This drug belongs to a class of drugs known as JAK inhibitors used to treat autoinflammatory conditions. One trial focuses on autoimmune skin conditions more common in Down syndrome. The second trial focuses on Down syndrome regression disorder , or DSRD, a rare but devastating neurological condition that can result in loss of speech, sleep disruptions, difficulty moving and hallucinations. There is evidence that suggests that a subset of DSRD cases may be caused by immune dysregulation affecting the brain .

Our study findings also support further investigation into the effects of interferon hyperactivity on fetal development more generally. Two of the key traits of Down syndrome that we found were affected by the tripling of interferon receptors – congenital heart disease and skull and facial shape – develop in utero.

Though our research shows promise on the potential of JAK inhibitors and other drugs that modulate the immune system to improve health outcomes in Down syndrome, more research in people is needed to determine their safety and efficacy.

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Down Syndrome Research Center

Rarely in basic or clinical research do we have the thrill of seeing results translated into therapies that transform lives. Such an opportunity now exists within the Stanford Institute of Neuro-innovation and Translational Neurosciences where critical discoveries in the laboratory are being translated into viable treatment strategies for patients and their families.

World Down Syndrome Day Celebration

Enjoy the company of other families as we celebrate our loved ones with Down syndrome! Activities will also include a Taiko Drum performance and a Sports Day with Stanford Athletes.  

Join the celebration!

CLICK BELOW TO SIGN UP (Families and Volunteers): 

WDSD Waiver (stanford.edu)

Stanford Down Syndrome Conference: Adult and Transition age topics

PROGRAM - CLICK HERE

Adult Medical - Peter Bulova, Director, Adult Down Syndrome Center, Univ of Pittsburgh/UPMC; Co-PI, Alzheimer's Biomarker Consortium-Down Syndrome, Pitt

Mental Health - Dennis McGuire, 28 years of clinical experience, served over 6000 teens and adults; authored “Mental Wellness of Adults with Down Syndrome"

Regression - Jon Santoro, nation's top expert on Down Syndrome Regression Disorder, Assoc Professor, Neurology, Keck School of Medicine, USC

College, Living, Employment, Legal options   - Leadership from California State Council on Developmental Disabilities, Think College and self advocates

Many thanks to: SVDSN, DSCBA, T21RS and The Matthew Foundation

For Video Recording - $129

2022 Down Syndrome Conference

DOWNLOAD PROGRAM and PRESENTATIONS  

Importance, Challenges, and Latest Interventions of Sleep

Rafael Pelayo , MD,  President, California Sleep Society and  Clinical Professor, Psychiatry & Behavioral Sciences, Stanford Center for Sleep Sciences Medicine

Caroline Okorie , MD, MPH,  Clinical Assistant Professor, Pediatrics – Pulmonary Medicine, Stanford School of Medicine

DOWNLOAD DR. PELAYO'S PRESENTATION

Download Dr. Okorie's Presentatation

Dual Diagnosis of Down syndrome and Autism

Noemi Spinazzi , Co-Chair, DSMIG DS-Autism Dual Diagnosis Subcommittee and Medical Director, UCSF Benioff Children’s Hospital Oakland Down syndrome clinic

Teresa Unnerstall, Author of “A New Course: A Mother’s Journey Navigating Down Syndrome And Autism”

Please visit The Matthew Foundation website for the presentation slides.

Do you want to get involved with the Down Syndrome Research Center?

Email: info_sdsrc [at] stanford.edu

Our Mission

Our mission is to help people with Down syndrome lead healthier and happier lives by rapidly and effectively applying research discoveries to useful treatments.

Down Syndrome Resources

Families with a member with Down syndrome face many challenges and have many questions.  We present on this website an extensive and curated collection of references, articles, blogs, news articles, and essays that will be valuable sources of information.

COVID-19 Information

Question and Answers (Q&A) on COVID-19 have been developed to help you support your loved one with Down syndrome. These documents have been endorsed by all the United States Down syndrome organizations, the Jerome Lejeune Foundation, and Trisomy 21 Research Society.

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Clinical Report Updates Recommendations for Care of Children With Down Syndrome: American Academy of Pediatrics

For release:, media contact:.

Lisa Black 630-626-6084 [email protected]

The American Academy of Pediatrics updates its recommendations for pediatricians and families affected by a diagnosis of Down syndrome within a clinical report, “ Health Supervision for Children and Adolescents With Down Syndrome ,” published in the May 2022 Pediatrics. Typically, a diagnosis of Down syndrome is confirmed by chromosome analysis or suspected by prenatal screening. The report (published online April 18) observes that Down syndrome is the most common chromosomal cause of intellectual disability, and that improvement in care and quality of life has increased the life expectancy of people with Down syndrome to average age 60. The report, written by the AAP Council on Genetics, covers questions concerning prenatal intervention and breaks down the care and treatment of children with Down syndrome by age. These children may have many co-occurring medical conditions and cognitive impairment, and while the level of social-emotional functioning may vary, these skills may be improved with early intervention and therapy through early adulthood. The authors emphasize that continuing research is critical for directing the care for optimal outcomes of people with Down syndrome.

The American Academy of Pediatrics is an organization of 67,000 primary care pediatricians, pediatric medical subspecialists and pediatric surgical specialists dedicated to the health, safety and well-being of infants, children, adolescents and young adults.

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Down Syndrome Research Program

• Our clinical program
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Contact Information

Phone: 617-726-7927

Explore This Research Program

We are a research team composed of enthusiastic healthcare providers committed to innovation in Down syndrome research. Our team is motivated to offer research opportunities that can help maximize the life potential for all people with Down syndrome. Working collaboratively with researchers around the globe, we are dedicated to advancing our shared understanding of biological processes associated with Down syndrome. To this extent, we are proud to offer families a portfolio of research opportunities.

Mission Statement

We are a collaborative, multidisciplinary team, serving people with Down syndrome of all ages and their families. We provide evidence-based clinical care, education, and cutting-edge research so that individuals with Down syndrome can reach their full potential.

Vision Statement

Our passion is to provide healthcare, research, and education that contribute to a world in which all people with Down syndrome are accepted, celebrated and have the opportunity to fully realize their potential.

Current Research Projects

Alzheimer's vaccine "abate" study.

The ABATE Study is testing an investigational vaccine for Alzheimer’s disease in people with Down syndrome. People with Down syndrome often get Alzheimer’s disease (a type of dementia) when they get older. Dementia is a disease that causes memory loss and other thinking problems. Dementia due to Alzheimer’s occurs when a protein called amyloid builds up in the brain. The ABATE Study is testing a vaccine against Alzheimer’s. We want to see if the vaccine is safe. We also want to see if it slows the progression of Alzheimer’s disease in people with Down syndrome. About 80 people with Down syndrome will take part in the ABATE Study. Who is eligible for the ABATE Study? You may be able to join this study if you:

• Have Down syndrome
• Are between 35 and 50 years old
• Have a study partner

Your study partner is someone who could support you during your participation. For example, they could be a family member or any relative close to you, or a carer. What is the study treatment? The study treatment, ACI-24.060, is a new vaccine which is not yet on the market. It may help to remove amyloid in the brain. This could slow down memory loss and thinking problems. In the ABATE Study, you will receive either the vaccine or an inactive vaccine (also called placebo). This is so we can see how the vaccine affects your body. Neither you nor the study team will know which vaccine you are getting. You will get the vaccine or inactive vaccine, as well as any tests and visits for the study, at no cost. What happens in the ABATE Study? The study lasts for about 2 years and is split into 3 parts:

• Screening Period: The study team will do tests to see if you meet the criteria to join the study. If you can join, you and your study partner will sign consent forms before you begin.
• Treatment Period: You will get either the vaccine or inactive vaccine 6 times. You will also have visits at the study clinic and phone calls so the study team can check your health and check how the vaccine is working in your body.
• Follow-up Period: You won’t get the vaccine or inactive vaccine anymore. You will have some visits to check your health and see how the vaccine is working in your body.

The ABATE study is sponsored by AC Immune and registered in the USA and Europe - ClinicalTrials.gov number NCT05462106 / EU CT Number 2022-500069-29-00.

If you are interested , please  complete this screening survey to find out if you meet the intial enrollment criteria.

You and your study partner can learn more by visiting Abate-study.com or by contacting us at 617-726-6297 or email [email protected].

Fluoxetine and Depression

Does your adult child with Down syndrome have symptoms of depression? The Massachusetts General Hospital at the Lurie Center is currently recruiting for a new research study that will evaluate the effectiveness and safety of the drug fluoxetine for the treatment of depression in adults with Down syndrome. Participants must be:

• 18 to 45 years of age
• diagnosed with Down syndrome
• have symptoms of depression

For more information, please contact Dr. Robyn Thom’s research staff at: (781) 860-1711 or [email protected].

Neuroimaging and EEG Research Study

We are conducting a research study to examine the effectiveness of transcranial photobiomodulation (tPBM) on improving language, memory and attention in adults with Down syndrome (ages 18-30 years). The study consists of 1 screening visit, approximately 3 study visits and 18 treatment sessions (3/week for 6 weeks). Study visits include neuropsychological testing, EEG testing, and MRI scans. You will be compensated up to $1,245 for participating and a stipend of $525 for cost of transportation. Caregivers will receive a stipend of $525.

If you are interested in participating, please contact us at 617-724-4539 or [email protected] .

Effects of Hypoglossal Nerve Stimulation on Cognition & Language in Down Syndrome

We are studying new ways to treat obstructive sleep apnea in children and young adults with Down syndrome who have persistent obstructive sleep apnea despite prior tonsillectomy. We will be researching how placement of an investigational surgically implanted nerve stimulator for the purpose of treating severe obstructive sleep apnea (OSA) improves the neurocognition and expressive language skills in children with Down syndrome, ages 10-21. This therapy has already been tested and approved by the FDA for use in adults meeting specific requirements. This research is being conducted at Massachusetts General Hospital and Massachusetts Eye and Ear Infirmary by Drs. Hartnick and Skotko. If you are interested in learning more about this study, and whether or not you/your child would be an appropriate candidate, please contact the research team by calling Dr. Hartnick at (617) 573-4206 or by email at [email protected] .

Developing a Down Syndrome Health Instrument

Primary caregivers are asked to participate in a survey about the health of individuals with Down syndrome. Although over 200,000 individuals with Down syndrome live in the United States, studies to date have focused on outcomes apart from health. We need to accurately measure the health of all individuals with DS – and there are not similar tools for this population available. Creating such an instrument will provide a barometer of the current state of health for DS and hold use in future research. We are creating an instrument that directly assesses health in DS – the Down syndrome Health Instrument (DHI). The goal of the DHI is to accurately measure the current health of an individual with Down syndrome.

To be eligible, you must (1) be the primary caregiver of an individual with Down syndrome (and the individual must be <22 years of age and not have mosaic DS), (2) you, the caregiver, must be ≥ 18 years of age, (3) be fluent in written and spoken English, and 4) be able to read and provide informed consent. Participation is completely voluntary, and you have the right to withdraw at any time.

Please email [email protected] or call 617-726-7927 if you are interested in participating.

Longitudinal Investigation for the Enrichment of Down Syndrome Research (LIFE-DSR)

Massachusetts General Hospital’s Down Syndrome Program is pleased to introduce our new study, the Longitudinal Investigation for Enhancing Down Syndrome Research (LIFE-DSR) in collaboration with LuMind IDSC. This study represents a milestone for Down syndrome research as it is the first study in LuMind’s Clinical Trials Network. LIFE-DSR is a natural history study that aims to better understand the progression of Alzheimer’s disease in those with Down syndrome.

The study will examine behavioral, cognitive, and health changes that may occur over the course of 2-3 years, with a focus on how these changes relate to the development of Alzheimer’s dementia. Alzheimer’s disease is an important topic in the DS community because by the age of 60 about 70% of those with DS will develop Alzheimer’s dementia, compared to the general population where only 10-12% of seniors develop the disease.

The goal of LIFE-DSR is to gather information in order to develop tools capable of measuring changes associated with Alzheimer’s disease in those with Down syndrome. LIFE-DSR will also collect blood samples to aid in the development of blood tests for Alzheimer’s Disease.

The recruitment is now closed but the study is on-going. You can find more information from the Lumind IDSC Clinical Trails Network .

Down Syndrome Patient Database

All current patients in the Down Syndrome Program at Massachusetts General Hospital are invited to participate in a research project to build an international national registry to track the health and medical history of people with Down syndrome across their lives. Health information will be collected from existing and future medical records, so there are no extra study visits or procedures. This Down Syndrome Patient Registry is taking place at Massachusetts General Hospital, as well as other centers around the United States and the world that specialize in Down syndrome clinical care and research.

Here are research publications that have resulted from this project:

Santoro SL, Cannon S, Capone G, Franklin C, Hart SJ, Hobensack V, Kishnani PS, Macklin EA, Manickam K, McCormick A, Nash P, Oreskovic NM, Patsiogiannis V, Steingass K, Torres A, Valentini D, Vellody K, Skotko BG (2019). Unexplained regression in Down syndrome: 35 cases from an international Down syndrome database. Genet Med., early view online .

Hart SJ, Zimmerman K, Linardic CM, Cannon S, Pastore A, Patsiogiannis V, Rossi P, Santoro SL, Skotko BG, Torres A, Valentini D, Vellody K, Worley G, Kishnani PS (2019). Detection of iron deficiency in children with Down syndrome. Genetics in Medicine, early view online.

Lavigne J, Sharr C, Elsharkawi I, Ozonoff A, Baumer N, Brasington C, Cannon S, Crissman B, Davidson E, Florez JC, Kishnani P, Lombardo A, Lyerly J, McDonough ME, Schwartz A, Berrier K, Sparks S, Stock-Guild K, Toler T, Vellody K, Voelz L, Skotko B. (2017). Thyroid dysfunction in patients with Down syndrome: Results from a multi-institutional registry study. American Journal of Medical Genetics Part A, 173A:1539-1545. Article .

Sharr C, Lavigne J, Elsharkawi IMA, Ozonoff A, Baumer N, Brasington C, Cannon S, Crissman B, Davidson E, Florez JC, Kishnani P, Lombardo A, Lyerly J, McDonough ME, Schwartz A, Berrier KL, Sparks S, Stock-Guild K, Toler TL, Vellody K, Voelz L, Skotko BG. (2016). Detecting celiac disease in patients with Down syndrome. American Journal of Medical Genetics, Part A 170A: 3098-3105. Article .

Lavigne, J., Sharr, C., Ozonoff, A., Prock, L.A., Baumer, N., Brasington, C., Cannon, S., Crissman, B., Davidson, E., Florez, J.C., Kishnani, P., Lombardo, A., Lyerly, J., McCannon, J.B., McDonough, M.E., Schwartz, A., Berrier, K.L., Sparks, S., Stock-Guild, K., Toler, T.L., Vellody, K., Voelz, L., Skotko, B.G. (2015). National Down syndrome patient database: Insights from the development of a multi-center registry study. American Journal of Medical Genetics Part A 167A:2520–2526. Article .

Completed Research Projects

Social networks of people with down syndrome.

Adults with Down syndrome, ages 25 and older, and their caregivers were asked to participate in a 30-minute interview. We developed a survey that measures individuals’ social networks. Your social network is the collection of friends and family with whom you engage on a regular basis.

The study included one 30-minute interview with a Study Coordinator, during which, we asked the adult with Down syndrome basic questions about him/herself and the people with whom he/she regularly connects. At the same time, the caregiver was asked to complete a 30-minute electronic questionnaire. The interview took place in person in a private meeting space at Massachusetts General Hospital or virtually. A year after the first study visit the questionnaire was repeated for both the participant and the caregiver. This study resulted in two publications:

• Harisinghani A, Dhand A, Steffensen EH, Skotko BG. Sustainability of personal social networks of people with Down syndrome. Am J Med Genet C Semin Med Genet. 2023 Sep 22:e32064. doi: 10.1002/ajmg.c.32064. Epub ahead of print. PMID: 37740458.
• Skotko BG, Krell K, Haugen K, Torres A, Nieves A, Dhand A. Personal social networks of people with Down syndrome. Am J Med Genet A. 2023 Mar;191(3):690-698. doi: 10.1002/ajmg.a.63059. Epub 2022 Nov 27. PMID: 36437642.

Engaging underserved families in the United States with Down Syndrome Clinic to You (DSC2U)

This research project is looking to identify barriers and find sustainable pathways to engage with Spanish-speaking and/or African American Down syndrome communities. Through this research project we hope to learn culturally appropriate ways for clinicians and researchers to engage Spanish-speaking and/or African American caregivers around the topic of health and wellness for people with Down syndrome. We believe that everyone should have access to excellent affordable, specialty care. Together, we are looking for ideas on how we might be able to bridge the gap of opportunity and access to health and wellness information. In order to do this, we are conducted focus groups, PCP interviews, and an online survey.

Phase I Clinical Trial: an investigational vaccine for treatment of Alzheimer’s disease in people with Down syndrome

It is well known that individuals with Down syndrome develop Alzheimer's at a much higher rate than the general population. This research study will test whether an investigational vaccine can affect Alzheimer's-related brain changes in Down syndrome.

The study was a randomized, placebo-controlled, double-blinded Phase I clinical trial. This means that study participants were randomly given either the active investigational vaccine or a non-active placebo that looks like the active drug; neither the participant nor the study personnel at our clinic knew who is receiving which one.

The study lasted 24 months, during which study participants visited the study clinic 22 times. At each visit, participants were asked how they are feeling, and, at some of the visits, they underwent medical exams, memory tests, blood tests, EKG, and brain imaging scans. The active participation phase of this trial is now complete.

Here is an educational video , explaining some of the preliminary results.

Physical Activity Assessment in Adults with Down Syndrome

Many adult patients with Down Syndrome are overweight or obese, and physical activity which can help with weight control is therefore a health priority in individuals with Down Syndrome. Objective information about physical activity level is not typically available for individuals with Down Syndrome, however, and patient-reported or caregiver-reported physical activity estimations are not always available or accurate. Adult subjects had an objective assessment of their physical activity measured using an accelerometer. This objective physical activity assessment helped us counsel patients on healthy lifestyles and weight management, and the individual data was pooled to help us better understand what physical activity patterns look like in this high risk patient population.

Predicting Obstructive Sleep Apnea in People with Down Syndrome

This project sought to develop a more efficient method of screening for obstructive sleep apnea (OSA) in individuals with Down syndrome. OSA is associated with a number of medical complications ranging from cognitive deficits to lung and heart disorders. Yet, while OSA is common among individuals with Down syndrome, the current method for diagnosing OSA—an overnight sleep study—can be uncomfortable, costly, and inconvenient for both patients and their families.

Here are the research publications that resulted from this project:

Elsharkawi I, Gozal D, Macklin EA, Voelz L, Weintraub G, Skotko BG. (2017). Urinary biomarkers and obstructive sleep apnea in patients with Down syndrome. Sleep Medicine, 34:84-89. Article . 

Jayaratne, Y.S.N., Elsharkawi, I., Macklin, E., Voelz, L., Weintraub, G., Rosen, D., Skotko, B.G. (2017). The facial morphology in Down syndrome: A 3D comparison of patients with and without obstructive sleep apnea. American Journal of Medical Genetics, Part A, 73(11):3013-3021. Article

Skotko BG, Macklin EA, Muselli M, Voelz L, McDonough ME, Davidson E, Allareddy V, Jayaratne YSN, Bruun R, Ching N, Weintraub G, Gozal D, Rosen D. (2017). A predictive model for obstructive sleep apnea and Down syndrome. American Journal of Medical Genetics Part A, 73(4):889-896. Article . Supplementary Materials .

Allareddy V, Ching N, Macklin EA, Voelz L, Weintraub G, Davidson E, Albers Prock L, Rosen D, Bruun, R, Skotko BG. (2016). Craniofacial features as assessed by lateral cephalometric measurements in children with Down syndrome. Progress in Orthodontics, 17(1):35. Article .

Nutrition and Weight Management in People with Down Syndrome

Nutrition and weight management are health priorities for individuals with Down syndrome. However, quantitative data is not always available to detail the burden of poor nutrition, prevalence of overweight/obesity in the Down syndrome community or possible solutions to these problems. This poster shares novel data collected from the Massachusetts General Hospital Down Syndrome Program patients. It discusses:

• The prevalence of overweight and obesity among children and adults seen in our program, including a comparison to statistics for the general population and other individuals with intellectual or developmental disabilities.
• The natural BMI trend of a sample of our patients over a 6-month period.
• The results of surveys completed by patients on their self-identified nutrition challenges, as well as their use of mobile technology.

View our research poster

ELND005 Drug Trial for People with Down Syndrome Is a Success

The results are now in: The Phase 2 clinical drug trial of ELND005, sponsored by Transition Therapeutics, was a success! As many of you know, our Down Syndrome Program at Massachusetts General Hospital was one of three sites in the country selected to participate in this landmark study. We are thankful to the six adults with Down syndrome, and their caregivers, who participated at our clinic. Read a summary of the study , and learn what this might mean for your son or daughter with Down syndrome in the future. The next step would be to test ELND005 in a Phase 3 clinical drug trial. At this time, the company has decided not to pursue this next step.

Here are the research publication that resulted from this project:

Rafii, M.S., Skotko, B.G., McDonough, M.E., Pulsifer, M., Evans, C., Doran, E.., Muranevici, G., Kesslak, P., Abushakrah, S., Lott, I., for the ELND005-DS Study Group. (2017). A Randomized, Double-Blind, Placebo-Controlled, Phase II Study of Oral ELND005 (scyllo-Inositol) in Young Adults with Down Syndrome without Dementia. Journal of Alzheimer’s Disease, 58:401–411. Article . Press release .

Santoro JD, Lee S, Mlynash M, Mayne EW, Rafii MS, Skotko BG (2020). Diminished Blood Pressure Profiles in Children With Down Syndrome. Hypertension (3):819-825. Article .

Mengel D, Liu W, Glynn RJ, Selkoe DJ, Strydom A, Lai F, Rosas HD, Torres A, Patsiogiannis V, Skotko B, Walsh DM (2020). Dynamics of plasma biomarkers in Down syndrome: the relative levels of Aβ42 decrease with age, whereas NT1 tau and NfL increase. Alzheimers Res Ther. 12(1):27. Article .

Antonarakis S, Skotko BG, Rafii MS, Strydom A, Pape SE, Bianchi DW, Sherman SL, Reeves RH (2020). Down syndrome. Nat Rev. Dis. Primers 6: 9. Article .

Crombag NM, Page-Christiaens GC, Skotko BG, de Graaf G (2020). Receiving the news of Down syndrome in the era of prenatal testing. Am J Med Genet A.182(2):374-385. Article . Press release .

Joslyn N, Berger H, Skotko BG (2019). Geospatial analyses of accessibility to Down syndrome specialty care. The Journal of Pediatrics (19) 31469-6. Article . Press release .

Ilacqua A, Benedict J, Shoben A, Skotko BG, Matthews T, Benson B, Allain DC (2019). Alzheimer’s disease development in adults with Down syndrome: Caregivers’ perspectives. Am J Med Genet Part A., early view online .

Tarui T, Im K, Madan N, Madankumar R, Skotko BG, Schwartz A, Sharr C, Ralston SJ, Kitano R, Akiyama S, Yun HJ, Grant E, Bianchi DW (2019). Quantitative MRI Analyses of Regional Brain Growth in Living Fetuses with Down Syndrome. Cerebral Cortex, early view online July 2, 2019 .

Skotko BG, Allyse, MA, Bajaj K, Best RG, Klugman S, Leach M, Meredith S, Michie M, Stoll K, Gregg, AR (2019). Adherence of cell-free DNA noninvasive prenatal screens to ACMG recommendations. Genetics in Medicine, Early view online . Supplementary material . Press release . Updated Assessments from Prenatal Research Information Consortium .

Skotko BG, Samuelson D, Kageleiry A, Lefebvre P, Hellstern M, Campbell J (2019). Comment on “The price of abandoning diagnostic testing for cell-free DNA screening.” Prenatal Diagnosis. 39(2):130. Comment .

De Graaf G, Levine SP, Goldstein R, Skotko BG (2019). Parents’ perceptions of functional abilities in people with Down syndrome. American Journal of Medical Genetics Part A. 179(2): 161-176. Article . Press release .

De Graaf G, Buckley F, Skotko BG (2018). Brith and population prevalence for Down syndrome in European countries. Poster at World Down Syndrome Congress convention, Glasgow, Scotland, July 25-27, 2018.

Santoro SL, Bartman T, Cua CL, Lemle S, Skotko BG (2018). Use of Electronic Health Record Integration for Down Syndrome Guidelines. Pediatrics 142(3). Article.

Lazar J, Woglom C, Chung J, Schwartz A, Hsieh Y, Moore R, Crowley D, Skotko B (2018). Co-Design process of a smart phone app to help people with Down syndrome manage their nutritional habits. Journal of Usability Studies 13(2): 73-93. Article .

Diercks GR, Wentland C, Keamy D, Kinane TB, Skotko BG, de Guzman V, Grealish E, John Dobrowski J, Soose R, Hartnick CJ (2017). Hypoglossal Nerve Stimulation in Adolescents With Down Syndrome and Obstructive Sleep Apnea. JAMA Otolaryngology-Head & Neck Surgery, 144(1):37-42 Article .

Hart S, Visootsak J, Tamburri P, Phuong P, Baumer N, Hernandez M-C, Skotko BG, Ochoa-Lubinoff C, D’Ardhuy X, Kishnani PS, Spiridigliozzi GA (2017). Pharmacological interventions to improve cognition and adaptive functioning in Down syndrome: Strides to date. American Journal of Medical Genetics Part A, 173(11):3029-3041, Article .

De Graaf, G., Buckley, F., Dever, J., Skotko, B.G. (2017). Estimation of live birth and population prevalence of Down syndrome in nine U.S. states. American Journal of Medical Genetics, Part A, 173(10):2710-2719, Article . Supplementary Material . Data for Figure 4 . Data for Figure 5 . Press release . Fact Sheet .

Rafii, M.S., Skotko, B.G., McDonough, M.E., Pulsifer, M., Evans, C., Doran, E.., Muranevici, G., Kesslak, P., Abushakrah, S., Lott, I., for the ELND005-DS Study Group. (2017). A Randomized, Double-Blind, Placebo-Controlled, Phase II Study of Oral ELND005 (scyllo-Inositol) in Young Adults with Down Syndrome without Dementia. Journal of Alzheimer’s Disease, 58:401–411. Article . Press release . Online information .

Allyse, M., Aypar, U., Bonhomme, N., Darilek, S., Doughtery, M., Farrell, R., Grody, W., Highsmith, W.E., Michie, M., Nunes, M., Otto, L., Pabst, R., Palomaki, G., Runke, C., Sharp, R.R., Skotko, B., Stoll, K. Wick, M. (2017). Offering Prenatal Screening in the Age of Genomic Medicine: A Practice Guide. Journal of Women’s Health, 26(7):755-761. Article .

Elsharkawi I, Gozal D, Macklin EA, Voelz L, Weintraub G, Skotko BG. (2017). Urinary biomarkers and obstructive sleep apnea in patients with Down syndrome. Sleep Medicine, 34:84-89. Article . Press release .

Skotko BG, Macklin EA, Muselli M, Voelz L, McDonough ME, Davidson E, Allareddy V, Jayaratne YSN, Bruun R, Ching N, Weintraub G, Gozal D, Rosen D. (2017). A predictive model for obstructive sleep apnea and Down syndrome. American Journal of Medical Genetics Part A, 73(4):889-896. Article . Supplementary Materials . Press release .

Kageleiry A, Samuelson D, Duh MS, Lefebvre P, Campbell J, Skotko BG. (2017). Out-of-pocket medical costs and third-party healthcare costs for children with Down syndrome. American Journal of Medical Genetics Part A, 173(3):627-637. Article . Press Release .

Group Members

Investigators

• Brian Skotko, MD, MPP
• Jeanhee Chung, MD
• Karen Donelan, ScD, EdM
• Casey Evans, PhD
• Jose Florez, MD, PhD
• Grace Hsieh, RN, PhD
• Stephen Lorenz
• Nicolas Oreskovic, MD
• Holly Parker
• Margaret Pulsifer, PhD
• Stephanie Santoro, MD
• Janet Sherman, PhD

Statistician

Eric Macklin, PhD

Research Assistants

• Ashlee Campbell
• Vasiliki Patsiogiannis

Program Manager

Amy Torres, BS [email protected] 617-726-7927

Publications

De Graaf, G., Buckley, F., Dever, J., Skotko, B.G. (2017). Estimation of live birth and population prevalence of Down syndrome in nine U.S. states. American Journal of Medical Genetics, Part A, 173(10):2710-2719, Article . Supplementary Material . Data for Figure 4 . Data for Figure 5 .  Fact Sheet .

Skotko BG, Macklin EA, Muselli M, Voelz L, McDonough ME, Davidson E, Allareddy V, Jayaratne YSN, Bruun R, Ching N, Weintraub G, Gozal D, Rosen D. (2017). A predictive model for obstructive sleep apnea and Down syndrome. American Journal of Medical Genetics Part A, 73(4):889-896. Article . Supplementary Materials . 

Kageleiry A, Samuelson D, Duh MS, Lefebvre P, Campbell J, Skotko BG. (2017). Out-of-pocket medical costs and third-party healthcare costs for children with Down syndrome. American Journal of Medical Genetics Part A, 173(3):627-637. Article . 

Allareddy V, Ching N, Macklin EA, Voelz L, Weintraub G, Davidson E, Albers Prock L, Rosen D, Bruun, R, Skotko BG. (2016). Craniofacial features as assessed by lateral cephalometric measurements in children with Down syndrome. Progress in Orthodontics, 17(1):35 . Article .

De Graaf G, Buckley F, Skotko B. (2016). Estimation of the number of people with Down syndrome in the United States. Genetics in Medicine . Early view online . Article. Fact Sheet .

Skotko, B.G., Tenenbaum, A. (2016). Down syndrome. In Rubin, I.L., Merrick, J., Greydanus, D.E., Patel, D.R. (Eds.) Health Care for People with Intellectual and Developmental Disabilities across the Lifespan. New York: Springer. Textbook .

Roberts, M., Skotko, B. (2016). Down syndrome. In Domino FJ (Ed.), www.5MinuteConsult.com , Philadelphia: Wolters Kluwer.

Anthony R. Gregg, Brian G. Skotko, Judith L. Benkendorf, Kristin G. Monaghan, Komal Bajaj, Robert G. Best, Susan Klugman, and Michael S. Watson; on behalf of the ACMG Noninvasive Prenatal Screening Work Group (2016). Noninvasive prenatal screening for fetal aneuploidy, 2016 update: a position statement of the American College of Medical Genetics and Genomics. Genetics in Medicine 18(10):1056-1065. Article .

Jacobs, J., Schwartz, A., McDougle, C., Skotko, B.G. (2016). Rapid Clinical Deterioration in an Individual with Down Syndrome. American Journal of Medical Genetics Part A 170(7): 1899–1902 . Article .

Diercks, G.R., Keamy D., Kinane, T.B., Skotko, B., Schwartz, A., Grealish, E., Dobrowski, J., Soose, R., Hartnick, C. (2016). Hypoglossal Nerve Stimulator Implantation in an Adolescent with Down Syndrome and Sleep Apnea. Pediatrics 137(5):e20153663. Article . Press release.

de Graaf, G., Buckley, F., Skotko, B.G. (2016). Live births, natural losses, and elective terminations with Down syndrome in Massachusetts. Genetics in Medicine 18: 459–466. Article .

Skotko, B.G., Levine, S.P., Macklin, E.A., Goldstein, R.D. (2016). Family perspectives about Down syndrome. American Journal of Medical Genetics Part A 170(4): 930–941. Article . 

de Graaf, G., Buckley, F., Skotko, B.G. (2015). Estimates of the live births, natural losses and elective terminations with down syndrome in the United States. American Journal of Medical Genetics, Part A 167A:756–767. Article . Supplementary Materials .

Grieco, J., Pulsifer, M., Seligsohn, K., Skotko, B., Schwartz, A. (2015). Down Syndrome: Cognitive and Behavioral Functioning Across the Lifespan. American Journal of Medical Genetics, Part C 169C:135-149. Article .

White, Melissa (2013). Providing Breastfeeding Support in the Hospital Setting for Mothers Who Have Infants With Down Syndrome. ICAN: Infant, Child, & Adolescent Nutrition. Article .

Gregg, A.R., Gross, S.J., Best, R.G., Monaghan, K.G., Bajaj, K., Skotko, B.G., Thompson, B.H., Watson, M.S., are the Noninvasive Prenatal Screening Working Group of the American College of Medical Genetics (2013). ACMG Statement on Noninvasive Prenatal Screening for Fetal Aneuploidy. Genetics in Medicine 15(5): 395-398. Article .

Skotko, B.G., Davidson, E.J., Weintraub, G.S. (2013). Contributions of a specialty clinic for children and adolescents with Down syndrome. American Journal of Medical Genetics, Part A 161(3):430-437. Article (English). Article (Español).

Schwartz, A. (2012) The ins & outs of transition planning . ( Article ) (pdf)

Leach, M., Skotko, B.G. (2012). Resources available for informed prenatal decisions. (Letter to the Editor). Genetics in Medicine: 14:348-349. Letter to the Editor .

Skotko, B.G., Leach, M. (2011). Physicians need to offer up-to-date information about Down syndrome to expectant couples to inform decision-making [E-letter]. Pediatrics. October 17, 2011.

Skotko, B.G., Levine, S.P., Goldstein, R. (2011). Having a Son or Daughter with Down Syndrome: Perspectives from Mothers and Fathers. American Journal of Medical Genetics Part A 155:2335-2347. Article . Press release .

Skotko, B.G., Levine, S.P., Goldstein, R. (2011). Having a Brother or Sister with Down Syndrome: Perspectives from Siblings. American Journal of Medical Genetics Part A: 155:2348-2359. Article . Press release .

Skotko, B.G., Levine, S.P., Goldstein, R. (2011). Self-perceptions from People with Down Syndrome. American Journal of Medical Genetics, Part A : 155:2360-2369. Article . Press release .

Rosen, D., Lombardo A., Skotko, B., Davidson, E.J. (2011). Parental perceptions of sleep disturbances and sleep-disordered breathing in children with Down syndrome. Clinical Pediatrics, 50:121-125. Article .

Skotko, B. (2009). "Driving Forward." In Thicker than Water: Essays by Adult Siblings of People with Disabilities. Ed. Don Meyer. Bethesda, MD: Amazon .

Skotko, B., Kishnani, P., & Capone, G. for the Down Syndrome Diagnosis Study Group (2009). Prenatal diagnosis of Down syndrome: How best to deliver the news. American Journal of Medical Genetics, Part A, 149A: 2361-2367. Article . Press release . Summary in Spanish .

Skotko, B., Capone, G., & Kishnani, P. for the Down Syndrome Diagnosis Study Group (2009). Postnatal diagnosis of Down syndrome: Synthesis of the evidence on how best to deliver the news. Pediatrics ,124: e751-e758. Article . Press release . Summary in Spanish .

Skotko, B. (2009). With new prenatal testing, will babies with Down syndrome slowly disappear? Archives of Disease in Childhood, 94: 823-826. Article .

Skotko, B. & Levine S. P. (2009). Fasten Your Seatbelt: A Crash Course on Down Syndrome for Brothers and Sisters . Bethesda, MD: Woodbine House .

Florez, J. (2007). Knowledge is power. (Article).  Journal of the American Medical Association, Vol 298, No.13

Skotko, B. (2007). Letter to the editor: First- and second-trimester evaluation of risk for Down syndrome. Obstetrics and Gynecology, 110: 1426. Article .

Skotko, B. (2006). Letter to the editor: A surprising postnatal diagnosis. Obstetrics and Gynecology, 108: 1297. Article .

Skotko, B., & Levine, P. (2006). What the other children are thinking: Brothers and sisters of persons with Down syndrome. American Journal of Medical Genetics Part C: Seminars in Medical Genetics , 142C:180-6.  Article , Press release .

Skotko, B. (2006). Words matter: The importance of nondirective language in first-trimester assessments for Down syndrome. American Journal of Obstetrics and Gynecology. 195:625-26. Article .

Skotko, B. (2006). Letter to the editor: Comparing Three Screening Strategies for Combining First- and Second-Trimester Down Syndrome Markers. Obstetrics & Gynecology. 107:1170. Article .

Skotko, B., Canal, R. (2006). Continuing a Pregnancy After Receiving a Prenatal Diagnosis of Down Syndrome in Spain. Progresos en Diagnostico y Tratamiento Prenatal. 17: 189-92. Article , English version . Survey.

Skotko, B. (2005). Mothers of children with Down syndrome reflect on their postnatal support.  Pediatrics . 115: 64-77. Article , Summary , Press Release , Survey.

Skotko, B. (2005). Prenatally diagnosed Down syndrome: Mothers who continued their pregnancies evaluate their health care providers. American Journal of Obstetrics & Gynecology, 192: 670-77. Article , Summary ,  Press Release, Survey.

Skotko, B., & Canal, R. (2005). Postnatal support for mothers of children with Down syndrome.  Mental Retardation , 43: 196-212. Article . Survey.

Skotko, B. (2005). Communicating the postnatal diagnosis of Down syndrome: An international call for change. Italian Journal of Pediatrics , 31: 237-243. Article , Press Release .

Skotko, B., & Canal, R. (2004). Apoyo postnatal para madres de niños con síndrome de Down.  Revista Síndrome de Down , 21: 54-71. Article .

Skotko, B. & Kidder C. (2001). Common Threads: Celebrating Life with Down Syndrome.  Rochester Hills: Band of Angels Press .

New Research Study

We are recruiting current adult patients for a study of social networks of people with Down syndrome.

Down Syndrome Clinical Program

Learn more about the Down Syndrome Program at Mass General, including prenatal services and clinics for infants and toddlers, school-aged children, adolescents and adults.

Support the Down Syndrome Program

Gifts from individuals help to support the hospital's three-part mission of innovative research and education in addition to patient care that is second to none.

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Shots - Health News

Scientists look to people with down syndrome to test alzheimer's drugs.

Jon Hamilton

Frank Stephens testifies at a Congressional hearing in 2017. Global Down Syndrome Foundation hide caption

Frank Stephens testifies at a Congressional hearing in 2017.

For Frank Stephens, 40, the effort to defeat Alzheimer's is personal.

One reason is that the disease has left his mother "almost childlike," he says. "It is very hard to see."

Also, as a person with Down syndrome, Stephens knows that he is likely to develop Alzheimer's much earlier than his mother did.

This form of memory loss is common — but most Americans don't know about it

So he raises money for Alzheimer's research through the Global Down Syndrome Foundation and he takes part in research studies through the group's Human Trisome Project.

Stephens' goal is to help find a drug that stops Alzheimer's.

"That would be amazing," he says. "I'm hoping I can do that for my mother."

Extra chromosome, extra risk

People with Down syndrome are highly sought after for Alzheimer's research studies because many develop the disease in their 40s and 50s, and most will get it if they live long enough.

The elevated risk for Alzheimer's comes from the extra copy of chromosome 21 carried by people with Down syndrome.

How a hyperactive cell in the brain might trigger Alzheimer's disease

This extra genetic code leads to intellectual disability. It also changes the brain in at least two ways that can lead to Alzheimer's, says Joaquin Espinosa , executive director of the Linda Crnic Institute for Down Syndrome and a professor at the University of Colorado's Anschutz Medical Campus.

As a result, he says, "People with Down Syndrome give us a unique opportunity to understand what modulates the severity and the progress of Alzheimer's disease."

A hyperactive immune system

Down syndrome is associated with a hyperactive immune system. That protects people with the condition from some cancers, but also leads to chronic inflammation.

"And of importance to Alzheimer's," Espinosa says, "they have brain inflammation across the lifespan."

There is growing evidence that brain inflammation plays an important role in Alzheimer's. So Espinosa and a team of researchers are looking for ways to keep the brain's immune system in check.

Research News

Youthful spinal fluid could help treat alzheimer's disease, study suggests.

"We are running clinical trials for immune modulating agents in Down syndrome," he says. "There is an active trial right now to tone down that response with a class of drugs known as JAK inhibitors ."

JAK (Janus kinase) inhibitors are used to reduce inflammation in people with rheumatoid arthritis and other autoimmune diseases.

Espinosa hopes these drugs can also reduce inflammation in the brain and cut the risk of Alzheimer's and he is trying the approach in people with Down syndrome.

Extra chromosome, extra amyloid

Another team at the Crnic Institute is taking a different approach to modulating the immune system.

Dr. Huntington Potter says the idea is to boost a special immune cell that "eat(s) up things that aren't supposed to be there."

One of those things is amyloid, the sticky, toxic substance that builds up in the brains of people with Alzheimer's. People with Down syndrome tend to have more amyloid in their brains because their extra chromosome includes genetic instructions to make the substance.

Potter hopes to prevent this with a drug called Leukine , which increases the number of immune cells that eat amyloid.

Doctors Worry That Memory Problems After COVID-19 May Set The Stage For Alzheimer's

Last year, he did a small study to establish that Leukine could safely be given to people with Alzheimer's.

"We did not expect to see a cognitive benefit," he says. "But three weeks of treatment with Leukine and the individuals actually improved in their cognition."

Those people did not have Down syndrome. But in March, Potter's team showed that Leukine also worked in mice that did have Down syndrome.

"That then allowed us to apply for a grant to study young adults with Down syndrome before they get Alzheimer's disease," he says.

They got the $4.6 million grant from the National Institute on Aging. Now they need to recruit young adults who have Down syndrome for the study.

That shouldn't be a problem, says Lina Patel , director of neurodevelopmental, cognitive and behavioral assessment at the Crnic Institute.

"The self-advocates that we work with really are proponents" of research, she says. "They see that it is directly impacting their lives and the lives of others."

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Trisomy 21 (Down Syndrome) News and Updates

1 - 10 of 80, how vision can support or delay learning in a child with down syndrome: part 3.

Published on Mar 06, 2023

Once an individual collects visual input from their environment, they must organize, interpret, evaluate this information to make decisions about how to interact with their environment.

Trisomy 21 Experts Present at Genetics Grand Rounds

Published on Oct 04, 2021

Trisomy 21 Program staff provide details on the joys and challenges of raising a child with Down syndrome to help genetic counselors better prepare families.

Something for Everyone

Published on Sep 04, 2019

The NDSC conference offers programs that will teach you something new, events where you can meet others who have shared in similar experiences and opportunities for memory making.

What's behind “The Lucky Few” Tattoo?

The tattoo is meant to be placed in an obvious spot to start a conversation about Down syndrome to spread awareness, promote inclusion, and educate others.

Learning the Latest; Gaining Empowerment

The annual NDSC Convention provides an opportunity for parents and family members, self-advocates, community advocates and professionals to learn the latest information on Down syndrome.

Participants Sought for Brain Imaging in Down Syndrome Study

Published on May 30, 2019

Researchers are recruiting children ages 7-11 for a new research study examining brain development in children with Down syndrome.

Brain Imaging Study Expanded to Include Children with Down Syndrome

The NIH recently awarded funding for an infant brain imaging study at CHOP to better understand brain and behavioral development in children with Down syndrome.

My Sister Eve

Having a sister with Down syndrome has taught one young woman more about life than school ever could. She shares her sister's teachings.

Exploring Learning and Memory in Down Syndrome

Researchers from Drexel University are leading several studies that aim to understand how children with Down syndrome learn and how to most effectively provide early intervention.

New Sleep Study Could Help Children with Down Syndrome

A new sleep study at CHOP could lead to new treatments for children with Down syndrome who have obstructive sleep apnea.

Colorado State University

College of health and human sciences.

Friday, March 15

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CSU-led $6.2M study to identify, improve interventions for young children with Down syndrome

By Mark Gokavi

Video by Ron Bend

A national study led by Colorado State University aims to dramatically improve intervention planning and early clinical care for young children with Down syndrome.  

The CSU Developmental Disabilities Research Laboratory recently launched “Project CAPE-abilities, or C ommunication A nd P lay E arly abilities.” Researchers say it is the first large-scale, comprehensive, longitudinal study of early foundations of communication and play and their relation to other biomedical conditions in this population.  

The $6.2 million, five-year study funded by a grant from the National Institutes of Health enables researchers to evaluate 225 children as young as 18 months old. Findings will inform early screening techniques for co-occurring conditions like autism or attention deficit hyperactivity disorder and will help clinicians identify children who may need more intensive intervention.  

“This project is aligned with the broader goal of answering priority questions in the communities that we study and serve,” said CSU Professor Deborah Fidler from the Department of Human Development and Family Studies. “We’re not interested in asking research questions where the findings will sit on the shelf and gather dust. We want to know what the priorities are. And then we want to use our research toolkit to provide added information that will be immediately used in clinical settings.”  

World Down Syndrome Day    

March 21, or 3-21, is World Down Syndrome Day because people with the condition have three copies of chromosome 21 instead of two. One in every 700 U.S.-born babies, or about 6,000 each year, has Down syndrome, according to the Centers for Disease Control and Prevention .  

In 2014, one of those babies was born to Elizabeth Jeub, who lives in Brighton. Her son Noah, 9, began life being fed by a tube to gain enough weight for open heart surgery at 3 months old.  

“ From birth to 3 years old, there’s so much going on, and a lot of it is just processing the diagnosis,” said Jeub, who helped found the Denver location of GiGi’s Playhouse , which offers free educational, therapeutic and career builder programs to children with Down syndrome.  

Challenges in existing research  

“ There are a lot of gaps. It is a huge learning curve,” Jeub said. “Having that data from research to inform what therapy is right for each child can benefit a lot of us in this group.”  

Findings from the CSU-led study will directly inform early screening practices and help clinicians identify which children may need more intensive intervention support as early as 18 months old.  

The research will involve 75 children in California, Massachusetts and Colorado, where parents can visit Fidler’s lab at CSU or the University of Colorado Anschutz Medical Campus in Aurora.  

The study includes 25 children at each location for three years in a row. All will be followed for three years with intermittent study visits. Interested families can call (970) 491-1969 or email [email protected].    

Down syndrome national study  

The collaboration is among CSU researchers Fidler and Susan Hepburn in the Department of Human Development and Family Studies and Mark Prince from the Department of Psychology, plus Harvard University’s Nicole Baumer, University of California-San Francisco’s Somer Bishop and Noemi Spinazzi, and CU Anschutz’s Lina Patel.  

Baumer is a medical doctor specializing in neurodevelopmental disabilities and the director of the Down syndrome program at Boston Children’s Hospital. Bishop is a professor in psychiatry and behavioral sciences. Spinazzi is a medical doctor and assistant professor of pediatrics in UCSF’s School of Medicine. Patel is an associate professor in psychiatry who works at Children’s Hospital Colorado at the Anschutz Medical Campus.  

“Families often want information about their child’s development, what it means for the future, and how they can best capitalize on strengths and support their child’s needs,” Baumer said. “There are a wide range of abilities among young children with Down syndrome, and this first-of-its kind study will allow us to better understand what factors influence development. ”  

Bishop said she is increasingly asked about other diagnoses in children with Down syndrome and that screening tools were not built with those considerations in mind.  

Early detection, early intervention  

“I t is critical that we develop better methods for assessing strengths and challenges in social-communication and play behaviors in children with varied developmental profiles,” Bishop said. “The prospective longitudinal design of this study will allow us to better understand how social-communication and play skills develop alongside cognitive, language and motor skills in children with global developmental delays.”  

Noah had occupational, speech and physical therapy before he was 6 months old and behavioral therapy starting at age 4. He has participated in CSU studies since infancy.  

Jeub said the experiences were invaluable.  

“Research for all parents can be intimidating,” she said. “But the folks at CSU make the experience of participating in research enjoyable. They make it applicable.”  

Noah enjoys writing and is proficient at math. On a sunny day in March, Noah hit balls off his T-ball stand to his mother. Family dog Coco wrangled a rope toy and tried not to get hit by Noah’s prodigious line drives.  

“Whether it be games that you can play early on to improve executive functioning and cognitive development or speech development, those are huge things,” Jeub said. “It helps parents to feel empowered in a world where something suddenly came into your life that you weren’t expecting that you don’t know about, and that you feel powerless in. We hope to keep working with them for years to come so that we can see the fruits of the research.”  

Resources for parents of Down syndrome children  

Fidler said decades-old studies didn’t include tools now available. Down syndrome research funding has lagged, making this study crucial to identify targeted interventions and treatments.  

“We are going to visit with families and their children and complete a very comprehensive set of activities to learn all about each child’s biomedical history and their early communication and play skills,” Fidler said. “And we know that for many young children with Down syndrome, these skills develop in ways that are aligned with their overall development.  

“Thinking and reasoning and information processing most often develop in alignment with communication skills and play skills. For some children, however, play and communication skills do not develop in alignment with overall development. Those children may be at an elevated likelihood for a co-occurring diagnosis.”  

Asked for advice for parents in a comparable situation, Jeub said: “Enjoy your children while they’re young. Don’t stress out about all the unknowns. They will meet those milestones and be off onto the next thing before you know it. So just enjoy where you’re at, because they will grow up and they all learn in their own time.”  

Advocating for Down syndrome funding

In February, CSU faculty member Deborah Fidler was invited by the Global Down Syndrome Foundation to lobby members of Congress to support a bill that would increase funding levels.   

If enacted, HR 7268, or The DeOndra Dixon INCLUDE Act of 2024 , would raise funding at the National Institutes of Health up to $250 million. Fidler was seated behind Global Down Syndrome Foundation CEO Michelle Sie Whitten as Whitten testified during a Congressional subcommittee about the importance of the funding increase.    

Read, watch more: Ram Scholars is an inclusive college program for adults with intellectual disabilities who want to build career-related skills. The first initiative includes agricultural work .  

The Department of Human Development and Family Studies is part of CSU’s College of Health and Human Sciences .  

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Mark Gokavi

Stereotypes, biases, and low expectations strongly affect every aspect of the lives of people with intellectual disabilities. They represent boundaries which limit their ambitions, opportunities at school, in the workplace, in sports, in their communities, friendships, and romantic relationships.  

" I discovered that in psychology there is a concept called “self-fulfilling prophecy”, whereby a teacher who thinks that a student cannot understand would just act accordingly and therefore they would not teach the student. And there you go: the prophecy self-fulfills. But in my opinion, there are no difficult or easy concepts, there is always a simple way to explain things. If I think of all the things that were not explained and taught to me, well I really get angry, " said Marta Sodano. Marta is a 29-year-old Italian woman with Down syndrome who spoke during the World Down Syndrome Day Conference at the United Nations.  

The self-fulfilling prophecy is a sociological and psychological concept, first described in 1948 by the U.S. sociologist Robert K. Merton, illustrating how people’s assumptions and expectations affect events to such an extent that the initial prophecy comes true. These are not abstract inconsequential actions but rather a mental process conducive to creating a situation that has tangible effects on one’s life and affects social circumstances.  

This, and Marta Sodano’s words, have inspired the film "ASSUME THAT I CAN”. The protagonist, a young woman with Down syndrome, challenges the low expectations others have of her and proposes a reversal of perspective: initially those around believe that she cannot drink a cocktail, be a boxer, study Shakespeare, live alone, achieve important goals. Then halfway through the film there’s a twist: the protagonist forcefully invites the viewer, and society at large, to think outside the box and use the self-fulfilling prophecy positively: if you believe in me, if you trust in me, you can have a positive impact, and then, maybe, I will achieve goals, even unexpected ones.  

  If a teacher believes their students can learn, challenges them, and finds the right strategies to teach their subject matter, most likely they will learn it. If a parent supports their child and gives them the ability to make their own choices, then their child is more likely to succeed in whatever they set their mind to. Similarly, if an employer or co-worker believes that a colleague who has Down syndrome can carry out a task and create the right environment for teaching and learning to take place, then maybe they will master it. It’s a profound shift in consciousness that goes beyond denouncing denied rights, calling on anyone who wishes to actively fight to realize inclusion for all.   

The international campaign started with CoorDown in Italy and is supported by several international associations that are simultaneously launching the film worldwide: Canadian Down Syndrome Society, National Down Syndrome Society, Global Down Syndrome Foundation, Down's Syndrome Association UK, Down Syndrome Australia, and New Zealand Down Syndrome Association with the participation of members of the Fundació Catalana Síndrome de Down.  

Starting today until March 21st, CoorDown, NDSS, and other international partners will broadcast the real experiences of people with Down syndrome and their families from all over the world, sharing examples of the types of stereotypes experienced and the biases they've overcome. These will be a series of videos on social media.  

The film “ASSUME THAT I CAN” will run on CoorDown’s channels and will be distributed on all of NDSS’ platforms. The campaign was born from the collaboration with the New York-based agency SMALL and was produced by Indiana Production and directed by Rich Lee , with Christopher Probst as director of photography. Music was composed and produced by Stabbiolo Music.    

The campaign’s official hashtags are #AssumeThatICan #EndTheStereotypes #WorldDownSyndromeDay #WDSD24.  

Madison Tevlin began her career at the age of 12 when her cover of John Legend’s “All of Me” went viral. Born and raised in Toronto, Canada, Madison is a model, advocate and actor. Her credits include: Mr. D, Who Do You Think I Am , hosting the red carpet at the Canadian Screen Awards, and her iconic role as Cosentino in the film Champions , starring Woody Harrelson and directed by Bobby Farrelly. Madison is the first person with Down syndrome to be nominated for a Canadian Screen Award - Best Host, Talk Show or Entertainment News. Madison is a member of Best Buddies International, she walked the runway as part of the Knix Confidence Tour, was the keynote speaker at the Dear Mom conference in Laguna Beach and received the Quincy Jones Exceptional Advocacy award in 2023 from the Global Down Syndrome Foundation. Madison was honored among 19 other honorees at the 2024 NDSS Gala & Auction. Madison loves to challenge misunderstandings, by presenting her own story as a person who has passions and goals and is capable of much more than people expect of her.  

Antonella Falugiani , President, CoorDown : «Changing the perspective with which we approach disability is the challenge launched by CoorDown for 2024. A new milestone that embraces the long journey made in 12 years of commitment to promoting the rights of people with Down syndrome with the Global Campaigns. We decided to launch a call to action, which aims to engage the whole society, not just our community, because disability really affects everyone, and everyone must be able to act to change the culture that produces discrimination. With the story of "Assume That I Can" we show how each of us can contribute to inclusion by listening and looking at people with Down syndrome, their needs and desires without warped filters. Only in this way can we tear down the walls that still limit the lives of people with intellectual disabilities».  

Luca Lorenzini and Luca Pannese , Executive Creative Directors, SMALL New York: « This year, we wanted to make a very different film than in previous years. Taking inspiration from a speech Marta Sodano gave to the United Nations a few years ago, we set out to give a strong message against prejudice. Thanks to Madison's great acting skills and versatility and the talent of director Rich Lee, we made a film full of energy that we hope will help break down the stereotypes that still restrict the dreams and plans of people with Down syndrome».  

Karim Bartoletti, Partner/MD/Executive Producer, Indiana Production: ««Every year, CoorDown, with their creative and production partners tries to disrupt perception on the world of disabilities with a campaign that can carry the weight of a strong creative insight that can shine a new light on stereotypes and biases that are part of the lives of people with Down syndrome - and all intellectual disabilities as a whole. We thought the insight of the campaign was so strong that we adopted it in every aspect of production. “You Assume that I will shoot this campaign like any other commercial that deals with disabilities?” “You assume we cannot find an actor or an actress that can carry the weight of the whole film on his or her shoulder?” “You assume we cannot get Rich Lee to direct it and Chris Probst to light it?” If we want to create awareness and break boundaries through the work that we create and produce, we need to do it ourselves. We assumed that we could and we certainly did, because it certainly shows in the originality and power and creative strength of this year’s Coordown World Down Syndrome Day campaign. We are very proud of how the “Assume that I can” campaign is unlike anything else we have seen or done before.»    

World Down Syndrome Day (WDSD) is an international awareness day officially declared by the UN General Assembly in December 2022. All are invited to observe World Down Syndrome Day to spread awareness and knowledge about Down syndrome, to create a new culture of diversity, and to promote respect and inclusion for all people with Down syndrome.   

The choice of the date 3/21 is not accidental: Down syndrome, also known as Trisomy 21, is characterized by the presence of an extra chromosome - three instead of two - in chromosome pair 21. The theme of this year's World Day is “End the stereotypes!” Stereotypes are harmful: for people with Down syndrome and intellectual disabilities.   

For more information, email Michelle Sagan at [email protected] . 

COORDOWN ODV  

The Coordinamento delle associazioni delle persone con sindrome di Down was established in 1987 with the aim of promoting communication actions shared among the various Italian organizations engaging in the protection and promotion of the rights of people who have Down syndrome, and today it is the official representative body interacting with all Institutions. Every second Sunday of October, CoorDown promotes the National Down Syndrome Day and on 21 March of every year the World Down Syndrome Day , also by producing international communication campaigns which over the years have been awarded as many as 23 Cannes lions, of which 9 golden, at the International Festival of Creativity.  

About NDSS  

Founded in 1979, the National Down Syndrome Society (NDSS) empowers individuals with Down syndrome and their families by driving policy change, providing resources, engaging with local communities, and shifting public perceptions. NDSS engages grassroots advocates at the federal, state, and local levels and creates resources to support individuals with Down syndrome, their families, and caregivers across the lifespan on topics including education, employment, health and wellness, and aging. NDSS founded the National Buddy Walk® Program in 1995 and hosts community engagement events throughout the country including the New York City Buddy Walk® and Times Square Video, the NDSS Adult Summit, and the Down Syndrome Advocacy Conference. Visit www.ndss.org to learn more.  

___________________  

CREDITS  

  AGENCY  

Agency: SMALL  

Executive Creative Directors: Luca Pannese, Luca Lorenzini  

Creative Director: Paolo Montanari  

Managing Director: Alberto Scorticati  

Account Manager: Chiara Guadagnini   

PRODUCTION COMPANY  

Production Company: Indiana Production S.p.A.  

Director: Rich Lee  

DP: Christopher Probst, ASC  

Executive Producer: Karim Bartoletti  

Senior Producer: Silvia Bergamaschi  

Assistant Producer: Luca Bettinetti  

1st AD: Andrew Coffing  

Editor: Luca Angeleri  

Original Music: Alessandro Cristofori and Diego Perugini for Stabbiolo Music  

Colorist: Danilo Vittori   

Post Production Audio : Bravagente  

Senior Post Producer : Alga Pastorelli  

Post Produzione Video: 22 Dogs   

SERVICE COMPANY SPAIN  

Service Company: Vivi Film  

Executive Producer: Carlos Soms  

Production coordinator: Nerea Soms  

Art Director: John Blud  

Stylist: Cris Urso  

Media Office CoorDown ODV  

Paola Amicucci   

[email protected]  

Tel. +39 345.7549218  

www.coordown.it  

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• Int J Mol Cell Med
• v.5(3); Summer 2016

Down Syndrome: Current Status, Challenges and Future Perspectives

Mohammad kazemi.

1 Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.

2 Medical Genetic Center of Genome, Isfahan, Iran.

3 Pediatric Inherited Diseases Research Center, Research Institute for Primordial Prevention of Non-communicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran.

Mansoor Salehi

Majid kheirollahi.

Down syndrome (DS) is a birth defect with huge medical and social costs, caused by trisomy of whole or part of chromosome 21. It is the most prevalent genetic disease worldwide and the common genetic cause of intellectual disabilities appearing in about 1 in 400-1500 newborns. Although the syndrome had been described thousands of years before, it was named after John Langdon Down who described its clinical description in 1866. Scientists have identified candidate genes that are involved in the formation of specific DS features. These advances in turn may help to develop targeted therapy for persons with trisomy 21. Screening for DS is an important part of routine prenatal care. Until recently, noninvasive screening for aneuploidy depends on the measurement of maternal serum analytes and ultrasonography. More recent progress has resulted in the development of noninvasive prenatal screening (NIPS) test using cell-free fetal DNA sequences isolated from a maternal blood sample. A review on those achievements is discussed.

Down syndrome (DS) is the most frequently occurring chromosomal abnormality in humans and affecting between 1 in 400-1500 babies born in different populations, depending on maternal age, and prenatal screening schedules ( 1 - 6 ). DS is the common genetic cause of intellectual disabilities worldwide and large numbers of patients throughout the world encounter various additional health issues, including heart defects, hematopoietic disorders and early-onset Alzheimer disease ( 7 - 9 ). The syndrome is due to trisomy of the whole or part of chromosome 21 in all or some cells of the body and the subsequent increase in expression due to gene dosage of the trisomic genes ( 10 ). It is coupled with mental retardation, congenital heart defects, gastrointestinal anomalies, weak neuromuscular tone, dysmorphic features of the head, neck and airways, audiovestibular and visual impairment, characteristic facial and physical features, hematopoietic disorders and a higher incidence of other medical disorders. The incidence of births of children with DS increases with the age of the mother. However, due to higher fertility rates in younger women, the probability of having a child with DS increases with the age of the mother and more than 80% of children with DS are born to women under 35 years of age ( 7 , 11 ).

Historical background

Approximately 2500 years ago, Bernal and Briceno thought that certain sculptures represented individuals with trisomy 21, making these potteries the first empirical indication for the existence of the disease ( Figure 1 ). Martinez-Frias identified the syndrome in 500 patients with Alzheimer disease in which the facial features of trisomy 21 are clearly displayed. Different scientists described evident illustration of the syndrome in 15 th and 16 th century paintings. Esquirol wrote phenotypic description of trisomy 21 in 1838. English physician, John Langdon Down explained the phenotype of children with common features noticeable from other children with mental retardation. He referred them “Mongoloids” because these children looked like people from Mongolia ( 12 - 15 ).

Down syndrome statue representing individual with trisomy 21 related to almost 2500 years ago (16)

This disease was named “Down Syndrome” in honor of John Langdon Down, the doctor who first recognized the syndrome in 1866 but until the middle of the 20 th century, the cause of DS remained unknown. The probability that trisomy 21 might be a result of a chromosomal abnormality was suggested in 1932 by Waardenburg and Davenport ( 12 , 17 ). A revolution finally took place in 1956, when Joe Hin Tjio and Albert Levan described a set of experimental situations that allowed them to precisely characterize the number of human chromosomes as 46. During the three years of the publication of this revolutionary work, Jerome Lejeune in France and Patricia Jacobs in the United States were able to identify an extra copy of chromosome 21 in karyotypes prepared from DS patients. Then, in the 1959, researchers finally determined that presence of an additional copy of chromosome 21 (referred to trisomy 21) is the cause of DS ( 1 , 18 ).

Genetic basis

Chromosome 21 is the smallest human autosome with 48 million nucleotides and depicts almost 1–1.5% of the human genome. The length of 21q is 33.5 Mb and 21 p is 5–15 Mb. More than 400 genes are estimated to be on chromosome 21 ( Table 1 ). Chromosome 21 has 40.06% repeat content comprising short interspersed repeatitive elements (SINEs), long interspersed repeatitive elements (LINEs), and long terminal repeats (LTRs) ( 3 , 11 , 19 ). The most acceptable theory for the pathogenesis of trisomy 21 is the gene-dosage hypothesis, which declares that all changes are due to the presence of an extra copy of chromosome 21 ( 12 ). Although it is difficult to select candidate genes for these phenotypes, data from transgenic mice suggest that only some genes on chromosome 21 may be involved in the phenotypes of DS and some gene products may be more sensitive to gene dosage imbalance than others. These gene products include morphogens, cell adhesion molecules, components of multi-subunit proteins, ligands and their receptors, transcription regulators and transporters. A “critical region” within 21q22 was thought to be responsible for several DS phenotypes including craniofacial abnormalities, congenital heart defects, clinodactyly of the fifth finger, mental retardation and several other features ( 3 , 11 ).

Candidate dosage sensitive genes on chromosome 21causing DS phenotype ( 11 , 23 , 24 )

DS is usually caused by an error in cell division named "nondisjunction" that leads to an embryo with three copies of chromosome 21. This type of DS is called trisomy 21 and accepted to be the major cause of DS, accounting for about 95% of cases ( 20 , 21 ). Since the late 1950s, scientists have also determined that a smaller number of DS cases (nearly 3-4%) are caused by chromosomal translocations. Because the translocations responsible for DS can be inherited, this form of the disease is sometimes named as familial DS. In these cases, a segment of chromosome 21 is transferred to another chromosome, usually chromosome 14 or 15. When the translocated chromosome with the extra piece of chromosome 21 is inherited together with two common copies of chromosome 21, DS will occur. For couples who have had one child with DS due to translocation trisomy 21, there may be an increased likelihood of DS in future pregnancies. This is because one of the parents may be a balanced carrier of the translocation. The chance of passing the translocation depends on the sex of the parent who carries the rearranged chromosome 21. If the father is the carrier, the risk is around 3 percent, while with the mother as the carrier, the risk is about 12 percent. This difference is due to the fact that it seems to be a selection against chromosomal abnormalities in sperm production which means men would produce fewer sperm with the wrong amount of DNA. Translocation and gonadal mosaicism are types of DS known to have a hereditary component and one third of them (or 1% of all cases of DS) are hereditary ( 1 , 22 ). The third form of disease named mosaicism, is a rare form (less than 2% of cases) of DS. While similar to simple trisomy 21, the difference is that the third copy of chromosome 21 is present in some, but not all cells. This type of DS is caused by abnormal cell division after fertilization. In cellular mosaicism, the mixture can be seen in different cells of the similar type; while with mosaicism, one set of cells may have normal chromosomes and another type may have trisomy 21 ( 1 , 22 )

Screening methods

Screening for DS is an important part of routine prenatal care. The most common screening method contains the measurement of a combination of factors: advanced maternal age, multiple second trimester serum markers, and second trimester ultrasonography ( Table 2 ) ( 25 - 26 ).

Detection rates and false positive rates of different Down syndrome screening tests ( 43 , 44 )

DR: detection rate; FPR: false-positive rate; NT: nuchal translucency; PAPP-A: pregnancy-associated plasma protein- A; β-hCG: chorionic gonadotropin; AFP: alpha-fetoprotein

The first method available for aneuploidy screening was maternal age. Advanced maternal age predisposes to DS and other fetal chromosomal abnormalities based on nondisjunction. In fact, the advanced maternal age was defined as age 35 years or older at delivery, because her risk of having a fetus with aneuploidy was equivalent to or more than the estimated risk for pregnancy loss caused by an amniocentesis. The extra chromosome 21 is the result of nondisjunction throughout meiosis in the egg or the sperm (standard trisomy 21) in almost 95% of individuals ( 27 - 29 ).

Trisomy 21 is coupled with a propensity for brachycephaly, duodenal atresia, cardiac defects, mild ventriculomegaly, nasal hypoplasia, echogenic bowel, mild hydronephrosis, shortening of the femur and sandal gap and clinodactyly or middle phalanx hypoplasia of the fifth finger. The first reported marker associated with DS was the thickening of the neck area ( 30 , 31 ). 40-50 percent of affected fetuses have a thickened nuchal fold measuring ≥ 6 mm in the second-trimester ( 32 , 33 ). After using of screening by nuchal translucency (NT), about 83% of trisomy 21 pregnancies were identified in the first trimester. Later, it was revealed that screening by a combination of maternal age, NT and bi-test [pregnancy-associated plasma protein (PAPP-A) with second trimester free β chorionic gonadotropin (β-hCG)] or tri-test [alpha-fetoprotein (AFP), estriol and free β-hCG] has a potential sensitivity of 94% for a 5% false-positive rate ( 34 - 36 ).

NT is a physiological process ‘marker’ in the fetus that reflects the fetal lymphatic and vascular development in the head and neck area. NT measurement was primarily used as a stand-alone test for aneuploidy screening. Later, maternal age was added, and finally, NT became part of a combined first trimester aneuploidy screening test (NT, maternal age and the maternal serum markers, PAPP-A and β-hCG) ( 35 ).

Pyelectasis which refers to a diameter of the renal pelvis measuring ≥ 4 mm, is another second trimester marker; in fact, renal dilatation has a higher occurrence among fetuses with DS. However, pyelectasis remains a minor marker as the sensitivity is about 17%-25%, with a false-positive rate of 2%-3% ( 37 ).

Another important soft marker that has been effectively combined into fetal abnormality screening is the nasal bone. The absence of nasal bone in fetus at the 11-14 weeks scan is related to DS. This marker, initially, was found in 73% of trisomy 21 fetuses and in only 0.5% of chromosomally normal fetuses ( 38 , 39 ) and, subsequently, it was estimated that the combination of maternal age, NT, maternal serum biochemical screening (by bi- test or tri- test) and examination of nasal bone could increase the detection rate to 97% ( 40 ). After the completion of further confirmation studies, it is generally accepted that fetal nasal bone is a worthy sonographic marker, even if there are racial differences in the length of this bone ( 41 - 42 ).

Noninvasive prenatal screening (NIPS)

One of the major innovations in obstetrical care was the introduction of prenatal genetic diagnosis, primarily by amniocentesis in the second trimester of pregnancy. Later, chorionic villus sampling during the first trimester allowed for earlier diagnosis. However, the potential risk of fetal loss due to an invasive procedure has urged the search for noninvasive approaches for genetic screening and diagnosis ( 45 ). More recent advances in genomics and related technologies have resulted in the development of a noninvasive prenatal screening (NIPS) test using cell-free fetal DNA sequences isolated from a maternal blood sample. Almost 4-10% of DNA in maternal serum is of fetal origin. Fetal trisomy detection by cfDNA from maternal blood has been done using massively parallel shotgun sequencing (MPSS). By next generation sequencing platforms, millions of amplified genetic fragments can be sequenced in parallel. MPSS detects higher relative amounts of DNA in maternal plasma from the fetal trisomic chromosome compared with reference chromo-somes. Platforms differ according to whether amplified regions throughout the genome, chromosome-specific regions, or single nucleotide polymorphisms (SNPs) are the targets for sequencing ( 1 , 45 , 46 ).

Another approach named digital analysis of selected regions (DANSR) selectively sequences loci only from target chromosomes by including a targeted amplification step. This method represents a considerable increase in sequencing efficiency. Recently, a new method has described selectively the sequences SNPs and ascertain copy number by comparing fetal to maternal SNP ratios between target and reference chromosomes. The use of SNPs may alleviate chromosome- to -chromosome amplification variability; however, the need for a reference chromosome partly negates this advantage ( 47 - 50 ).

Although studies are hopeful and exhibit high sensitivity and specificity with low false- positive rates, there are drawbacks to NIPS. Specificity and sensitivity are not consistent for all chromosomes; this is due to different content of cytosine and guanine nucleotide pairs. False- positive screening results take place and because the sequences derived from NIPS are derived from the placenta, like in chorionic villus sampling (CVS), they may not reflect the true fetal karyotype. Therefore, currently invasive testing is recommended for confirmation of a positive screening test and should remain an option for patients seeking a definitive diagnosis ( 35 , 45 , 51 ).

NIPS for fetal aneuploidy was presented into clinical practice in November 2011. Obstetricians have rapidly accepted this testing, and patients have welcomed this option due to its lack of fetal morbidity and mortality ( 52 ). At first, NIPS began as a screen for only trisomy 21 (T21) and was rapidly developed to include other common aneuploidies for chromosomes 13 (T13), 18 (T18), X, and Y ( 53 ).

Notwithstanding improvement in sensitivity, approaches using cfDNA are not diagnostic tests as false positive and false negative results are still generated, although at very low rates than the previous maternal screening tests. A significant source of a discrepant result comes from the fact that the fetal fraction of cfDNA originates pre-dominantly from apoptosis of the trophoblast layer of the chorionic villi and not the fetus. Thus, inva-sive diagnostic testing such as CVS or amnio-centesis, is recommended after a positive cfDNA fetal aneuploidy screening test. Because cfDNA testing is normally presented in the first trimester, CVS is often the choice invasive method applied. If mosaicism is recognized on CVS, confirmatory amniocentesis is recommended ( 54 - 56 ).

Although NIPS is not a diagnostic test, it offers a considerably developed screen for fetal aneuploidy compared to the earlier screening tests that depend on maternal serum markers ( Table3 ). Patients with positive screen results should take suitable genetic counseling to persuade that follow-up testing is necessary before making a decision as to whether or not to continue a pregnancy because of concern over a positive NIPS result. However, patients with negative test results need to know that there is still a chance that their fetus may have a chromosome abnormality due to a false negative result ( 52 ).

Detection rates and false positive rates of major aneuploidies using NIPT ( 51 , 57 , 58 )

CI: confidence interval.

Diagnostic methods

Amniocentesis is the most conventional invasive prenatal diagnostic method accepted in the world. Amniocenteses are mostly performed to acquire amniotic fluid for karyotyping from 15 weeks onwards. Amniocentesis performed before 15 weeks of pregnancy is referred to as early amniocentesis. CVS is usually performed between 11 and 13 (13+6) weeks of gestation and includes aspiration or biopsy of placental villi. Amniocentesis and CVS are quite reliable but increase the risk of miscarriage up to 0.5 to 1% compared with the background risk ( 59 - 60 ).

There is no medical cure for DS. However, children with DS would benefit from early medical support and developmental interventions initiation during childhood. Children with DS may benefit from speech therapy, physical therapy and work-related therapy. They may receive special education and assistance in school. Life expectancy for people with DS has improved noticeably in recent decades ( 61 ). Nowadays, cardiac surgery, vaccinations, antibiotics, thyroid hormones, leukemia therapies, and anticonvulsive drugs (e.g, vigabatrin) have significantly improved the quality of life of individuals with DS. Actually, life expectancy that was hardly 30 years in the 1960s is now increasing more than 60 years of age ( 3 , 62 - 63 ).

X inactivation is the mammalian dosage compensation mechanism that ensures that all cells in males and females have one active X chromoso-me (Xa) for a diploid set of autosomes. This is achieved by silencing one of the two X chromoso-mes in female cells. The X chromosome silencing is effected by Xist non-coding RNA and is associated with chromatin modification ( 64 ). Recently, resear-chers have applied this model of transcriptional silencing to the problem of additional gene expre-ssion in DS. In induced pluripotent stem (iPS) cells derived from a patient with DS, the researchers used zinc-finger nucleases to insert inducible X inactive specific transcript (non–protein-encoding) (XIST) into chromosome 21. The mechanism of transcriptional silencing due to the Xist transgene appears to involve covering chromosome 21 with Xist RNA that results in stable modification of heterochromatin. In the iPS cells, induction of the newly inserted transgene resulted in expression of XIST noncoding RNA that coated chromosome 21 and triggered chromosome inactivation ( 65 - 66 ).

In summary, DS is a birth defect with huge medical and social costs and at this time there is no medical cure for DS. So, it is necessary to screen all pregnant women for DS. NIPS for fetal aneuploidy which was presented into clinical practice since November 2011 has not been yet considered as diagnostic test as false positive and false negative test results are still generated. Thus, invasive diagnostic testing such as CVS or amniocentesis, is recommended after a positive cfDNA fetal aneuploidy screening test.

The described performance of screening for trisomy 21 by the cffDNA test, with a diagnostic rate of more than 99% and false positive rate less than 0.1%, is preferable to other screening methods. Despite the test is obtaining common acceptability, the high cost restricts its application to all patients, identified as such by another traditional first-line method of screening. In the screening with cffDNA testing, the nuchal scan is considered to be the most appropriate first-line method of screening.

Conflict of interest

The authors declared no conflict of interest.

Childhood Myeloid Proliferations Associated With Down Syndrome Treatment (PDQ®)–Health Professional Version

General information about childhood myeloid proliferations associated with down syndrome.

Myeloid leukemias that arise in children with Down syndrome, particularly in patients younger than 4 years, are a distinct subset of acute myeloid leukemia (AML) characterized by the co-existence of trisomy 21 and GATA1 mutations within the leukemic blasts that are often, but not always, megakaryoblastic.

This distinct leukemia is further subdivided into two types:[ 1 ]

• Transient abnormal myelopoiesis (TAM): A transient newborn and young-infant version, which spontaneously remits over time.
• Myeloid leukemia of Down syndrome (MLDS): An unremitting but chemosensitive version that appears later, between the ages of 90 days and 3 years.

It is important to recognize the possibility of these versions in both children with Down syndrome phenotypes and in those who have mosaic trisomy 21, which can be solely present in the leukemic blasts. If possible, newborns with apparent AML should not begin therapy until genetic testing results have been returned.[ 2 ]

In older children with megakaryocytic AML, it is important to rule out the presence of co-existing trisomy 21 and GATA1 mutations. These children may be successfully treated with the lower-intensity chemotherapy regimens that are used for children with myeloid leukemia associated with Down syndrome.[ 3 ]

• Lange B: The management of neoplastic disorders of haematopoiesis in children with Down's syndrome. Br J Haematol 110 (3): 512-24, 2000.  [PUBMED Abstract]
• Gamis AS, Smith FO: Transient myeloproliferative disorder in children with Down syndrome: clarity to this enigmatic disorder. Br J Haematol 159 (3): 277-87, 2012.  [PUBMED Abstract]
• de Rooij JD, Branstetter C, Ma J, et al.: Pediatric non-Down syndrome acute megakaryoblastic leukemia is characterized by distinct genomic subsets with varying outcomes. Nat Genet 49 (3): 451-456, 2017.  [PUBMED Abstract]

Transient Abnormal Myelopoiesis (TAM) Associated With Down Syndrome

Approximately 10% of neonates with Down syndrome develop TAM (also termed transient myeloproliferative disorder [TMD]).[ 1 ] This disorder mimics congenital AML but typically improves spontaneously within the first 3 months of life (median, 49 days). However, TAM has been reported to remit as late as 20 months.[ 2 ] The late remissions likely reflect a persistent hepatomegaly from TAM-associated hepatic fibrosis rather than active disease.[ 3 ]

Clinical Presentation and Risk Groups

Although TAM is usually a self-resolving condition, it can be associated with significant morbidity and may be fatal in 10% to 17% of affected infants.[ 2 - 6 ] When TAM is detected, it is either in a proliferative, worsening phase or it has already converted to a resolving, improving phase. Observation over time is needed to determine which phase is present. Infants with progressive organomegaly, visceral effusions, preterm delivery (less than 37 weeks of gestation), bleeding diatheses, failure of spontaneous remission, laboratory evidence of progressive liver dysfunction (elevated direct bilirubin), renal failure, and very high white blood cell (WBC) count are at particularly high risk of early mortality.[ 3 , 4 , 6 ] In one report, death occurred in 21% of these patients with high-risk TAM, although only 10% were attributable to TAM. The remaining deaths were caused by coexisting conditions known to be more prominent in neonates with Down syndrome.[ 3 ]

The following three risk groups have been identified on the basis of the diagnostic clinical findings of hepatomegaly with or without life-threatening symptoms:[ 3 ]

• Low risk. Includes those without hepatomegaly or life-threatening symptoms (38% of patients and an overall survival [OS] rate of 92% ± 8%).
• Intermediate risk. Includes those with hepatomegaly alone (40% of patients and an OS rate of 77% ± 12%).
• High risk. Includes those with hepatomegaly and life-threatening symptoms (21% of patients and an OS rate of 51% ± 19%).

Molecular Features

Genomics of tam.

TAM blasts most commonly have megakaryoblastic differentiation characteristics and distinctive mutations involving the GATA1 gene in the presence of trisomy 21.[ 7 , 8 ] TAM may occur in phenotypically normal infants with genetic mosaicism in the bone marrow for trisomy 21. While TAM is generally not characterized by cytogenetic abnormalities other than trisomy 21, the presence of additional cytogenetic findings may predict an increased risk of developing subsequent AML.[ 4 ]

GATA1 mutations are present in most, if not all, children with Down syndrome who have either transient abnormal myelopoiesis (TAM) or acute megakaryoblastic leukemia (AMKL).[ 7 , 9 - 11 ] GATA1 is a transcription factor that is required for normal development of erythroid cells, megakaryocytes, eosinophils, and mast cells. X-linked GATA1 mutations result in the absence of the full-length GATA1 protein, leaving only the normally minor variant, a truncated GATA1s transcription factor that has decreased activity.[ 7 , 8 ] This confers increased sensitivity to cytarabine by down-regulating cytidine deaminase expression, possibly providing an explanation for the superior outcome of children with Down syndrome and M7 AML when treated with cytarabine-containing regimens.[ 12 ]

Approximately 20% of infants with TAM and Down syndrome eventually develop AML. Most of these cases are diagnosed within the first 3 years of life.[ 4 , 8 ]

Treatment of TAM

While observation is appropriate for most infants with TAM, therapeutic intervention is warranted in patients with apparent severe hydrops or organ failure. Because TAM eventually spontaneously remits, treatment is short in duration and primarily aimed at the reduction of leukemic burden and resolution of immediate symptoms. Several treatment approaches have been used, including the following:

• Exchange transfusion.
• Leukapheresis.
• Low-dose cytarabine. Of these approaches, only cytarabine has been shown to consistently reduce TAM complications and related mortality.[ 3 , 6 ]; [ 13 ][ Level of evidence B4 ] Cytarabine dosing has ranged from 0.4 to 1.5 mg/kg per dose given intravenously (IV) or subcutaneously (SC) once to twice daily for 4 to 12 days.[ 6 ] This dosing schedule has produced similar efficacies and less toxicity than higher doses given in continuous 5-day infusions, which led to prolonged severe neutropenia.[ 3 ] A prospective trial examined the use of low-dose cytarabine (1.5 mg/kg per day IV or SC for 7 days) to treat symptomatic patients. This trial reported a significant reduction in early death using this regimen, compared with similar patients in the historical control group (12% ± 5% vs. 33% ± 7%, respectively; P = .02).[ 13 ][ Level of evidence B4 ]

Risk Factors for the Development of AML After Resolution of TAM

Subsequent development of myeloid leukemia of Down syndrome (MLDS) is seen in 10% to 30% of children with TAM. It has been reported at a mean age of 16 months (range, 1–30 months).[ 2 , 3 , 14 ] While TAM is generally not characterized by cytogenetic abnormalities other than trisomy 21, the presence of additional cytogenetic findings may connote an increased risk of developing subsequent MLDS.[ 4 ] An additional risk factor reported in two studies is the late resolution of TAM, measured by either time to complete resolution of signs of TAM (defined as resolution beyond the median, 47 days from diagnosis) or by persistence of minimal residual disease (MRD) in the peripheral blood at week 12 of follow-up.[ 3 ]; [ 13 ][ Level of evidence B4 ]

The use of cytarabine for TAM symptoms or persistent MRD in TAM has failed to show a reduction in later MLDS, as reported in large observational cohort studies.[ 3 , 6 ] In a prospective single-arm trial designed to assess whether cytarabine treatment for TAM could prevent the development of later MLDS, no benefit was found when compared with historical controls (19% ± 4% vs. 22% ± 4%, respectively; P = .88).[ 13 ][ Level of evidence B4 ]

• Homans AC, Verissimo AM, Vlacha V: Transient abnormal myelopoiesis of infancy associated with trisomy 21. Am J Pediatr Hematol Oncol 15 (4): 392-9, 1993.  [PUBMED Abstract]
• Gamis AS, Alonzo TA, Gerbing RB, et al.: Natural history of transient myeloproliferative disorder clinically diagnosed in Down syndrome neonates: a report from the Children's Oncology Group Study A2971. Blood 118 (26): 6752-9; quiz 6996, 2011.  [PUBMED Abstract]
• Massey GV, Zipursky A, Chang MN, et al.: A prospective study of the natural history of transient leukemia (TL) in neonates with Down syndrome (DS): Children's Oncology Group (COG) study POG-9481. Blood 107 (12): 4606-13, 2006.  [PUBMED Abstract]
• Muramatsu H, Kato K, Watanabe N, et al.: Risk factors for early death in neonates with Down syndrome and transient leukaemia. Br J Haematol 142 (4): 610-5, 2008.  [PUBMED Abstract]
• Klusmann JH, Creutzig U, Zimmermann M, et al.: Treatment and prognostic impact of transient leukemia in neonates with Down syndrome. Blood 111 (6): 2991-8, 2008.  [PUBMED Abstract]
• Hitzler JK, Cheung J, Li Y, et al.: GATA1 mutations in transient leukemia and acute megakaryoblastic leukemia of Down syndrome. Blood 101 (11): 4301-4, 2003.  [PUBMED Abstract]
• Mundschau G, Gurbuxani S, Gamis AS, et al.: Mutagenesis of GATA1 is an initiating event in Down syndrome leukemogenesis. Blood 101 (11): 4298-300, 2003.  [PUBMED Abstract]
• Groet J, McElwaine S, Spinelli M, et al.: Acquired mutations in GATA1 in neonates with Down's syndrome with transient myeloid disorder. Lancet 361 (9369): 1617-20, 2003.  [PUBMED Abstract]
• Rainis L, Bercovich D, Strehl S, et al.: Mutations in exon 2 of GATA1 are early events in megakaryocytic malignancies associated with trisomy 21. Blood 102 (3): 981-6, 2003.  [PUBMED Abstract]
• Wechsler J, Greene M, McDevitt MA, et al.: Acquired mutations in GATA1 in the megakaryoblastic leukemia of Down syndrome. Nat Genet 32 (1): 148-52, 2002.  [PUBMED Abstract]
• Ge Y, Stout ML, Tatman DA, et al.: GATA1, cytidine deaminase, and the high cure rate of Down syndrome children with acute megakaryocytic leukemia. J Natl Cancer Inst 97 (3): 226-31, 2005.  [PUBMED Abstract]
• Flasinski M, Scheibke K, Zimmermann M, et al.: Low-dose cytarabine to prevent myeloid leukemia in children with Down syndrome: TMD Prevention 2007 study. Blood Adv 2 (13): 1532-1540, 2018.  [PUBMED Abstract]
• Ravindranath Y, Abella E, Krischer JP, et al.: Acute myeloid leukemia (AML) in Down's syndrome is highly responsive to chemotherapy: experience on Pediatric Oncology Group AML Study 8498. Blood 80 (9): 2210-4, 1992.  [PUBMED Abstract]

Myeloid Leukemia of Down Syndrome (MLDS)

General information.

Children with Down syndrome have a 10-fold to 45-fold increased risk of leukemia when compared with children without Down syndrome.[ 1 ] However, the ratio of acute lymphoblastic leukemia to acute myeloid leukemia (AML) is typical for childhood acute leukemia. The exception is during the first 3 years of life, when AML, particularly the megakaryoblastic subtype, predominates and exhibits a distinctive biology characterized by GATA1 mutations and increased sensitivity to cytarabine.[ 2 - 7 ] Importantly, these risks appear to be similar whether a child has phenotypic characteristics of Down syndrome or whether a child has only genetic bone marrow mosaicism.[ 8 ]

Prognosis of Children With MLDS

Outcome is generally favorable for children with Down syndrome who develop AML. This is called myeloid leukemia of Down syndrome (MLDS) in the World Health Organization (WHO) classification.[ 9 - 11 ] For more information, see the sections on General Information About Childhood Myeloid Malignancies and World Health Organization (WHO) Classification System for Childhood AML in Childhood Acute Myeloid Leukemia Treatment.

Prognostic factors for children with MLDS include the following:

• Age. The prognosis is particularly good (event-free survival [EFS] rates exceeding 85%) in children aged 4 years or younger at diagnosis. This age group accounts for the vast majority of patients with MLDS.[ 10 - 13 ] Children with MLDS who are older than 4 years have a significantly worse prognosis. These patients should undergo the therapy that is used in children with AML without Down syndrome, unless a GATA1 mutation is found.[ 14 ]
• White blood cell (WBC) count. A large international Berlin-Frankfurt-Münster (BFM) retrospective study of 451 children with MLDS (aged >6 months and <5 years) observed a 7-year EFS rate of 78% and a 7-year overall survival (OS) rate of 79%. In multivariate analyses, WBC count (≥20 × 10 9 /L) and age (>3 years) were independent predictors of lower EFS. The 7-year EFS rate for the older population (>3 years) and for the higher WBC-count population still exceeded 60%.[ 15 ]
• AML karyotype. The presence of trisomy 8 has been shown to adversely impact prognosis.[ 13 ] In another study, complex karyotypes (≥3 independent abnormalities) were associated with an increased cumulative incidence of relapse (CIR) rate at 2 years (30.8% compared with 7.5% in patients without complex karyotypes; P = .001).[ 16 ]
• Minimal residual disease (MRD). MRD at the end of induction 1 was found to be a strong prognostic factor.[ 11 , 17 ] This finding was consistent with the BFM finding that early response correlated with improved OS.[ 13 ] However, a negative MRD status at the end of induction 1 did not identify a favorable-risk group of patients who could receive reduced chemotherapy.[ 16 ]

Approximately 29% to 47% of patients with Down syndrome present with myelodysplastic neoplasms (MDS) (<20% blasts) but their outcomes are similar to those with AML.[ 10 , 11 , 13 ]

Treatment of Newly Diagnosed Childhood MLDS

Appropriate therapy for younger children (aged ≤4 years) with MLDS is less intensive than current standard childhood AML therapy. Hematopoietic stem cell transplant is not indicated in first remission.[ 4 , 9 - 14 , 18 , 19 ]

Treatment options for newly diagnosed children with MLDS include the following:

• Chemotherapy.

Evidence (chemotherapy):

• When compared with the previous trial, these changes resulted in an overall improvement of approximately 10%.
• The EFS rate was 89.9%, and the OS rate was 93%.
• Relapse occurred in 14 patients and there were two treatment-related deaths, both related to pneumonia, neither of which occurred during induction 2.
• No patient had central nervous system (CNS) involvement in this trial or the preceding COG A2971 trial.[ 10 ]
• The only prognostic factor identified was MRD using flow cytometry on day 28 of induction 1. Among those who were MRD negative (≤0.01%), the disease-free survival (DFS) rate was 92.7%. In the 14.4% of patients who were MRD positive, the DFS rate was 76.2% ( P = .011).
• Outcomes were no worse despite reduction in chemotherapy. The OS rate was 89% (± 3%), and the EFS rate was 87% (± 3%), similar to that observed in AML-BFM 98 (OS rate, 90% ± 4% [ P = NS]; EFS rate, 89% ± 4% [ P = NS]). The CIR rate was 6% in both trials.
• Nine patients relapsed, and seven of those patients died.
• Patients with a good early response (<5% blasts by morphology before induction cycle 2, n = 123 [72%]) had better outcomes (OS rate, 92% ± 3% vs. 57% ± 16%, P < .0001; EFS rate, 88% ± 3% vs. 58% ± 16%, P = .0008; and CIR rate, 3% ± 2% vs. 27% ± 18%, P = .003).
• Less toxicity was seen in this trial, and treatment-related mortality remained low (2.9% vs. 5%, P = .276).

The following two prognostic factors were identified:[ 13 ]

• Trisomy 8 was an adverse factor (n = 37; OS rate, 77% vs. 95%, P = .07; EFS rate, 73% ± 8% vs. 91% ± 4%, P = .018; CIR rate, 16% ± 7% vs. 3% ± 2%, P = .02).
• This was confirmed in multivariate analysis, where lack of good early response and trisomy 8 maintained their adverse impact on relapse, with relative risks of 8.55 (95% confidence interval [CI], 1.96–37.29; P = .004) and 4.36 (95% CI, 1.24–15.39; P = .022), respectively.

Children with mosaicism for trisomy 21 are treated similarly to those children with clinically evident Down syndrome.[ 8 , 10 , 20 ] Children with MLDS who are older than 4 years have a significantly worse prognosis.[ 14 ] Although an optimal treatment for these children has not been defined, they are usually treated with AML regimens designed for children without Down syndrome.

Treatment options under clinical evaluation

Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website . For information about clinical trials sponsored by other organizations, see the ClinicalTrials.gov website .

Treatment of Relapsed or Refractory Childhood MLDS

A small number of trials address outcomes in children with MLDS who relapse after initial therapy or who have refractory MLDS. In three prospective trials of children with newly diagnosed MLDS, outcomes were poor for those who relapsed (4 of 11, 2 of 9, and 2 of 12 patients who relapsed survived).[ 9 , 13 , 16 ] Thus, these children are treated similarly to children without Down syndrome, with an intensive reinduction chemotherapy regimen. If a remission is achieved, therapy is followed by an allogeneic hematopoietic stem cell transplant (HSCT).

Treatment options for children with refractory or relapsed MLDS include the following:

• Chemotherapy, which may be followed by an allogeneic HSCT.

Evidence (treatment of children with refractory or relapsed MLDS):

• In contrast to the excellent outcomes achieved after initial therapy, only 50% of the children attained a second remission, and the 3-year OS rate was 26%. Attainment of second remission was more successful the later the relapse occurred after completing initial therapies.
• Approximately one-half of the children underwent allogeneic transplant, and no advantage was noted for transplant compared with chemotherapy. However, the number of patients was small.
• A similarly poor outcome, with a 3-year OS rate of 19%.
• The main cause of failure after transplant was relapse, which exceeded 60%. Survival was significantly worse for patients who relapsed early.
• The transplant-related mortality was approximately 20%.
• A Japanese registry study reported better survival after transplant of children with MLDS using reduced-intensity conditioning regimens compared with myeloablative approaches. However, the number of patients was very small (n = 5), and the efficacy of reduced-intensity approaches in children with MLDS requires further study.[ 23 ][ Level of evidence C2 ]
• Marlow EC, Ducore J, Kwan ML, et al.: Leukemia Risk in a Cohort of 3.9 Million Children with and without Down Syndrome. J Pediatr 234: 172-180.e3, 2021.  [PUBMED Abstract]
• Ravindranath Y: Down syndrome and leukemia: new insights into the epidemiology, pathogenesis, and treatment. Pediatr Blood Cancer 44 (1): 1-7, 2005.  [PUBMED Abstract]
• Ross JA, Spector LG, Robison LL, et al.: Epidemiology of leukemia in children with Down syndrome. Pediatr Blood Cancer 44 (1): 8-12, 2005.  [PUBMED Abstract]
• Gamis AS: Acute myeloid leukemia and Down syndrome evolution of modern therapy--state of the art review. Pediatr Blood Cancer 44 (1): 13-20, 2005.  [PUBMED Abstract]
• Taub JW, Ge Y: Down syndrome, drug metabolism and chromosome 21. Pediatr Blood Cancer 44 (1): 33-9, 2005.  [PUBMED Abstract]
• Crispino JD: GATA1 mutations in Down syndrome: implications for biology and diagnosis of children with transient myeloproliferative disorder and acute megakaryoblastic leukemia. Pediatr Blood Cancer 44 (1): 40-4, 2005.  [PUBMED Abstract]
• Kudo K, Hama A, Kojima S, et al.: Mosaic Down syndrome-associated acute myeloid leukemia does not require high-dose cytarabine treatment for induction and consolidation therapy. Int J Hematol 91 (4): 630-5, 2010.  [PUBMED Abstract]
• Lange BJ, Kobrinsky N, Barnard DR, et al.: Distinctive demography, biology, and outcome of acute myeloid leukemia and myelodysplastic syndrome in children with Down syndrome: Children's Cancer Group Studies 2861 and 2891. Blood 91 (2): 608-15, 1998.  [PUBMED Abstract]
• Sorrell AD, Alonzo TA, Hilden JM, et al.: Favorable survival maintained in children who have myeloid leukemia associated with Down syndrome using reduced-dose chemotherapy on Children's Oncology Group trial A2971: a report from the Children's Oncology Group. Cancer 118 (19): 4806-14, 2012.  [PUBMED Abstract]
• Taub JW, Berman JN, Hitzler JK, et al.: Improved outcomes for myeloid leukemia of Down syndrome: a report from the Children's Oncology Group AAML0431 trial. Blood 129 (25): 3304-3313, 2017.  [PUBMED Abstract]
• Creutzig U, Reinhardt D, Diekamp S, et al.: AML patients with Down syndrome have a high cure rate with AML-BFM therapy with reduced dose intensity. Leukemia 19 (8): 1355-60, 2005.  [PUBMED Abstract]
• Uffmann M, Rasche M, Zimmermann M, et al.: Therapy reduction in patients with Down syndrome and myeloid leukemia: the international ML-DS 2006 trial. Blood 129 (25): 3314-3321, 2017.  [PUBMED Abstract]
• Gamis AS, Woods WG, Alonzo TA, et al.: Increased age at diagnosis has a significantly negative effect on outcome in children with Down syndrome and acute myeloid leukemia: a report from the Children's Cancer Group Study 2891. J Clin Oncol 21 (18): 3415-22, 2003.  [PUBMED Abstract]
• Blink M, Zimmermann M, von Neuhoff C, et al.: Normal karyotype is a poor prognostic factor in myeloid leukemia of Down syndrome: a retrospective, international study. Haematologica 99 (2): 299-307, 2014.  [PUBMED Abstract]
• Hitzler J, Alonzo T, Gerbing R, et al.: High-dose AraC is essential for the treatment of ML-DS independent of postinduction MRD: results of the COG AAML1531 trial. Blood 138 (23): 2337-2346, 2021.  [PUBMED Abstract]
• Taga T, Tanaka S, Hasegawa D, et al.: Post-induction MRD by FCM and GATA1-PCR are significant prognostic factors for myeloid leukemia of Down syndrome. Leukemia 35 (9): 2508-2516, 2021.  [PUBMED Abstract]
• Taga T, Shimomura Y, Horikoshi Y, et al.: Continuous and high-dose cytarabine combined chemotherapy in children with down syndrome and acute myeloid leukemia: Report from the Japanese children's cancer and leukemia study group (JCCLSG) AML 9805 down study. Pediatr Blood Cancer 57 (1): 36-40, 2011.  [PUBMED Abstract]
• Taga T, Saito AM, Kudo K, et al.: Clinical characteristics and outcome of refractory/relapsed myeloid leukemia in children with Down syndrome. Blood 120 (9): 1810-5, 2012.  [PUBMED Abstract]
• Hitzler JK, He W, Doyle J, et al.: Outcome of transplantation for acute myelogenous leukemia in children with Down syndrome. Biol Blood Marrow Transplant 19 (6): 893-7, 2013.  [PUBMED Abstract]
• Muramatsu H, Sakaguchi H, Taga T, et al.: Reduced intensity conditioning in allogeneic stem cell transplantation for AML with Down syndrome. Pediatr Blood Cancer 61 (5): 925-7, 2014.  [PUBMED Abstract]

Latest Updates to This Summary (03/06/2024)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

This is a new summary.

This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board , which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.

About This PDQ Summary

Purpose of this summary.

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood myeloid proliferations associated with Down syndrome. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board , which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

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The lead reviewers for Childhood Myeloid Proliferations Associated With Down Syndrome Treatment are:

• Alan Scott Gamis, MD, MPH (Children's Mercy Hospital)
• Karen J. Marcus, MD, FACR (Dana-Farber Cancer Institute/Boston Children's Hospital)
• Jessica Pollard, MD (Dana-Farber/Boston Children's Cancer and Blood Disorders Center)
• Michael A. Pulsipher, MD (Children's Hospital Los Angeles)
• Rachel E. Rau, MD (Texas Medical Center)
• Lewis B. Silverman, MD (Dana-Farber Cancer Institute/Boston Children's Hospital)
• Malcolm A. Smith, MD, PhD (National Cancer Institute)
• Sarah K. Tasian, MD (Children's Hospital of Philadelphia)

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Global Down Syndrome Foundation Applauds House Energy & Commerce Committee for Advancing Legislation to Authorize Down Syndrome Research Program at NIH

Denver, CO, March 12, 2024 (GLOBE NEWSWIRE) -- The Global Down Syndrome Foundation (GLOBAL) praised the House Energy and Commerce Health Subcommittee for approving the DeOndra Dixon INCLUDE Project Act of 2024 (H.R. 7406), which would authorize the INvestigation of Co-occurring conditions across the Lifespan to Understand Down syndromE (INCLUDE) Project at the National Institutes of Health (NIH). 

The legislation will formally authorize a trans-NIH structure to ensure that major crosscutting issues and opportunities within Down syndrome research are identified and allow for multiple institutes to collaborate on a research plan. This will enable institute coordination to plan, fund, and share and disseminate research results that aim to improve health outcomes for those with Down syndrome.

GLOBAL is deeply grateful to their congressional champions who are co-sponsoring this important legislation: Representative Cathy McMorris Rodgers (R-WA) who formally introduced the game-changing DeOndra Dixon INCLUDE Project Act of 2024 with her colleagues Diana DeGette (D-CO), Tom Cole (R-OK), Rosa DeLauro (D-CT), Pete Stauber (R-MN) and Delegate Eleanor Norton Homes (D-DC) as original cosponsors.

GLOBAL will be launching a digital campaign  this week to encourage supporters to contact their Representatives, tell their personal stories, and let them know that passing  this bill this year is imperative and important Visit www.globaldownsyndrome.org/advocacy for more information.

“Working with Congresswoman Cathy McMorris Rodgers has been one of the greatest honors of my life,” says Michelle Sie Whitten, GLOBAL President & CEO. “With this bill, named in memory of our beloved Ambassador DeOndra Dixon, Congresswoman McMorris Rodgers is helping to create a powerful future for a population that has been largely ignored and neglected. With her unwavering commitment and leadership, and with wonderful bipartisan support, our champions are ensuring the INCLUDE Project and Down syndrome research funding remains a national priority and that we will see increased lifespan and improved health as a result.”

Having advocated for the establishment of INCLUDE, GLOBAL continues to advocate for additional funding and programs that would help some of the most vulnerable populations within the Down syndrome community: including those living in rural America, Black or African Americans with Down syndrome and other minorities. There is some research that points to a significant disparity in lifespan for Black or African Americans with Down syndrome as compared to a Caucasian with Down syndrome.

The INCLUDE Project was established via congressional directive in 2018 after a seminal first-in-kind House Appropriations Labor, Health and Human Services, and Education Subcommittee hearing led by then-Chairman Cole Tom Cole and Ranking Member Rosa DeLauro. Congresswoman McMorris Rodgers was a key supporter at the hearing and testified along with Crnic Institute for Down Syndrome Executive Director, Dr. Joaquín Espinosa, and GLOBAL Board Member and self-advocate, Frank Stephens. Frank’s testimony that day, which included the famous phrase, “I am a man with Down syndrome and my life’s worth living,” went viral to 1 million views that day and today stands at well over 200 million.

Dr. Espinosa’s testimony focused on the fact that people with Down syndrome have a very different disease profile whereby they are highly predisposed to certain diseases (for example Alzheimer’s and certain autoimmune diseases) and highly protected from others (for example solid tumors). He also presented his groundbreaking study that categorizes Down syndrome as an immune system disorder and how by studying people with Down syndrome we can not only improve their lives but the lives of millions of others who suffer from diseases.

Before Congress began funding the NIH INCLUDE Project, Down syndrome was one of the least funded genetic conditions by the NIH despite being the leading cause of developmental delay in the U.S. and around the world. For nearly two decades the funding had languished between $16 million and $20 million even during years when there was a double-digit growth of the NIH budget. In 2023, the estimated INCLUDE budget is $144 million. GLOBAL’s advocacy goal is to increase funding to over $250 million a year.

GLOBAL Affiliate, the Crnic Institute for Down Syndrome, has five clinical trials specifically for patients with Down syndrome: Two in Alzheimer’s and Down Syndrome, one in Down Syndrome Regression Disorder, and two in autoimmunity and inflammation.

To read about the impactful research that the INCLUDE Project has funded visit the NIH Down Syndrome Coordinating Center Website at: https://includedcc.org/.

About Global Down Syndrome Foundation

The Global Down Syndrome Foundation (GLOBAL) is the largest non-profit in the U.S. working to save lives and dramatically improve health outcomes for people with Down syndrome. GLOBAL has donated more than $32 million to establish the first Down syndrome research institute supporting over 400 scientists and over 2,200 patients with Down syndrome from 33 states and 10 countries. Working closely with Congress and the National Institutes of Health, GLOBAL is the lead advocacy organization in the U.S. for Down syndrome research and care. GLOBAL has a membership of over 100 Down syndrome organizations worldwide, and is part of a network of Affiliates – the Crnic Institute for Down Syndrome, the Sie Center for Down Syndrome, and the University of Colorado Alzheimer’s and Cognition Center – all on the Anschutz Medical Campus. 

GLOBAL’s widely circulated medical publications include Global Medical Care Guidelines for Adults with Down Syndrome, Prenatal & Newborn Down Syndrome Information and the award-winning magazine Down Syndrome World TM   . GLOBAL also organizes the annual AcceptAbility Gala in Washington DC, and the annual Be Beautiful Be Yourself Fashion Show, the largest Down syndrome fundraiser in the world. Visit globaldownsyndrome.org and follow us on social media (Facebook & Twitter: @GDSFoundation, Instagram: @globaldownsyndrome).

Attachments

• Congresswoman Cathy McMorris Rogers and GLOBAL Ambassador and Self-Advocate DeOndra Dixon
• RIGHT: GLOBAL President & CEO Michelle Sie Whitten, Paul Tonko (D-NY), GLOBAL Board Member & Self-Advocate Frank Stephens and Kevin Brennan