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OBJECTIVE: To assess the impact of treatment with orthodontic aligners (OA) on oral health-related quality of life (OHRQoL) in patients with trisomy 21 (T21) compared to non-syndromic patients. MATERIALS AND METHODS: The sample consisted of 30 patients, both sexes, aged between 11 and 35 years, divided into two groups: T21 (n = 10, patients with T21, treated prospectively) and CONTROL (n = 20, control group, non-syndromic patients, from the Orthodontic Laboratory of UNOPAR). In both groups, patients were treated with Invisalign orthodontic aligners (Align Technology), following the same treatment parameters. Participants, assisted by their caregivers, when necessary, answered Oral Health Impact Profile (OHIP-14) instrument and the patient's guardians answered the Oral Health Scale for People with Down's syndrome (OHDS) instrument, before (T0) and after 30 (T1), 180 (T2), and 365 (T3) days from the start of treatment. Friedman tests with Bonferroni correction and Mann-Whitney tests were used (p < .05). RESULTS: For the OHDS instrument, it was observed that for the eating and communication domains and an overall score, the treatment with OA positively impacted the lives of T21 patients (p < .05). Regarding the OHIP-14 instrument, the intragroup evaluation showed that in the CONTROL group, there was no significant difference between the evaluated times; while for the T21 group, there was a significant positive impact (p < .05). CONCLUSION: The results showed that the treatment with aligners positively impacted the OHRQoL of T21 patients, and these results were perceived by caregivers, mainly in relation to issues related to eating and communication.

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Chromosomal rearrangements can interfere with the disjunction and segregation of other chromosome pairs not involved in the rearrangements, promoting the occurrence of numerical abnormalities in resulting gametes and predisposition to trisomy in offspring. This phenomenon of interference is known as the interchromosomal effect (ICE). Here we report a prenatal case potentially generated by ICE. The first-trimester screening ultrasound of the pregnant woman was normal, but the NIPT indicated a high risk for three copies of chromosome 21, thus suspecting trisomy 21 (T21). After a comprehensive clinical evaluation and genetic counseling, the couple decided to undergo amniocentesis. The prenatal karyotype confirmed T21 but also showed a balanced translocation between the long arm of chromosome 15 (q22) and the long arm of chromosome 22. The parents' karyotypes also showed that the mother had the 15;22 translocation. We reviewed T21 screening methods, and we performed a literature review on ICE, a generally overlooked phenomenon. We observed that ours is the first report of a prenatal case potentially due to ICE derived from the mother. The recurrence risk of aneuploidy in the offspring of translocated individuals is likely slightly increased, but it is not possible to estimate to what extent. In addition to supporting observations, there are still open questions such as, how frequent is ICE? How much is the aneuploidy risk altered by ICE?

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Apraxia of speech is a persistent speech motor disorder that affects speech intelligibility. Studies on speech motor disorders with transcranial Direct Current Stimulation (tDCS) have been mostly directed toward examining post-stroke aphasia. Only a few tDCS studies have focused on apraxia of speech or childhood apraxia of speech (CAS), and no study has investigated individuals with CAS and Trisomy 21 (T21, Down syndrome). This N-of-1 randomized trial examined the effects of tDCS combined with a motor learning task in developmental apraxia of speech co-existing with T21 (ReBEC RBR-5435x9). The accuracy of speech sound production of nonsense words (NSWs) during Rapid Syllable Transition Training (ReST) over 10 sessions of anodal tDCS (1.5 mA, 25 cm) over Broca's area with the cathode over the contralateral region was compared to 10 sessions of sham-tDCS and four control sessions in a 20-year-old male individual with T21 presenting moderate-severe childhood apraxia of speech (CAS). The accuracy for NSW production progressively improved (gain of 40%) under tDCS (sham-tDCS and control sessions showed < 20% gain). A decrease in speech severity from moderate-severe to mild-moderate indicated transfer effects in speech production. Speech accuracy under tDCS was correlated with Wernicke's area activation (P3 current source density), which in turn was correlated with the activation of the left supramarginal gyrus and the Sylvian parietal-temporal junction. Repetitive bihemispheric tDCS paired with ReST may have facilitated speech sound acquisition in a young adult with T21 and CAS, possibly through activating brain regions required for phonological working memory.

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[This corrects the article DOI: 10.3389/fped.2023.1151797.].

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Background: The consequences of obesity are ominous, yet healthcare professionals are not adequately preventing or treating obesity in youth with Down syndrome (DS). Total daily energy expenditure (TDEE) is the energy expended in 24 h through physical activity and life-sustaining physiologic processes. An individual's TDEE is essential for determining the daily caloric intake needed to maintain or change body weight. Successful prevention and treatment of obesity in youth with DS is severely compromised by the lack of data on TDEE and information on weight-related behaviors for this high-risk population. This manuscript describes the protocol for the federally funded study that is in process to determine daily energy expenditure in a large cohort of children with DS. Methods: This observational cross-sectional study will include a national sample of 230 youth with DS, stratified by age (5-11 and 12-18 years of age) and sex. Doubly Labeled Water analysis will provide the criterion body fat%, fat-free mass, and TDEE. To increase accessibility and decrease the burden on participants, the entire study, including obtaining consent and data collection, is conducted virtually within the participant's home environment on weekdays and weekends. The study team supervises all data collection via a video conferencing platform, e.g., Zoom. This study will (1) examine and determine average TDEE based on age and sex, (2) develop a prediction equation based on measured TDEE to predict energy requirements with a best-fit model based on fat-free mass, sex, age, and height and/or weight, and (3) use 24-hour dietary recalls, a nutrition and physical activity screener, wearable devices, and sleep questionnaire to describe the patterns and quality of dietary intake, sleep, and physical activity status in youth with DS. Discussion: The lack of accurate information on energy expenditure and weight-related behaviors in youth with DS significantly impedes the successful prevention and treatment of obesity for this vulnerable population. The findings of this study will provide a further understanding of weight-related behaviors as obesity risk factors, currently not well understood for this population. This study will advance the science of weight management in individuals with disabilities and shift clinical practice paradigms.

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Sleep is a major concern, especially in people with Down Syndrome (DS). Beyond Obstructive Sleep Apnea, a number of other sleep difficulties have been reported in children with DS, such as delayed sleep onset, night-time awakenings, and early morning awakenings. The detrimental effect of sleep difficulties seems to contribute to and exacerbate the cognitive and behavioral outcomes of DS. Although the screening for sleep disorders is recommended early in age in DS, only a few studies have evaluated the sleep profile in preschool-age children with DS. The aim of the current study was to assess the association between sleep disturbances and behavioral problems in a group of preschool-age children with DS, by means of a feasible and easy-to-administer parent-report questionnaires. Seventy-one preschool-age children with DS, ranging in age from 3 to 5.11 years, were included in this retrospective study. Sleep disturbances were evaluated by means of the Sleep Disturbance Scale for Children, while emotional and behavioral problems by means of the Child Behavior Checklist. Sleep breathing disorders were the most frequent sleep difficulties reported by parents. Moreover, children with clinical scores in total sleep problems exhibited elevation of psychopathological symptoms, namely Total problems, Affective problems, Anxiety problems, Pervasive Developmental Problems, and Attention Deficit/Hyperactivity Problems. The identification of the broader connection between sleep difficulties and emotional and behavioral problems in preschool-age children with DS leads to important considerations for intervention.

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Background: Children with Trisomy 21 (T21) are at an increased risk of sleep-disordered breathing (SDB), which can impact daily functioning and cause other health complications. Accordingly, it is imperative to diagnose and treat SDB in this population. Current guidelines recommend screening polysomnogram by age 4 or sooner if clinically indicated. There are limited published studies describing characteristics of SDB in children with T21, particularly in infants and young children. Objective: The objective of this study is to characterize SDB and treatment modalities in infants and young children with T21. Methods: This is a retrospective review of a cohort of children (≤60 months of age) with T21 who completed a polysomnogram (PSG) between 2015 and 2020 at a pediatric referral center. Demographic information, relevant medical history, polysomnography parameters, and treatment details of these children were collected from EMR. Descriptive and comparative statistics were calculated for the cohort; additional subgroup analysis was completed by age 0-35 months and 36-60 months. Results: Most of the cohort met criteria for sleep apnea (84.1%), and airway surgery was the most common treatment modality (71.4%). The mean AHI was high (21.4 events/hour) with a trend towards hypoventilation (mean EtCO2 = 55.9 mmHg; mean percentage of TST with EtCO2 > 50 mmHg 20.8%). Mean arousal index was elevated (32 events/hour). There were no significant differences in SDB by age when we compared children 0-35 months and 36-60 months. Conclusions: This cohort of referred children with T21 showed high prevalence of SDB with a trend towards hypoventilation and disrupted sleep quality with no significant differences by age. These data highlight the importance of maintaining a high index of suspicion for SDB in young patients with T21 and obtaining PSG testing to characterize sleep and breathing.

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Introduction: Children and adolescents with intellectual disability (ID) exhibit higher rates of oppositional defiant disorder (ODD) than typically developing (TD) peers. However, studies focusing on the investigation of ODD prevalence in youth with Down syndrome (DS) are still limited. Methods: The current study aimed to investigate the prevalence of ODD clinical and subclinical symptoms in a group of 101 youth with DS (63 boys, 38 girls) ranging in age from 6 to 18 years. Moreover, the prevalence of ODD symptoms, as detected by means of three parent-report questionnaires, was compared with that detected by a semi-structured psychopathological interview, namely, the Schedule for Affective Disorders and Schizophrenia for School Aged Children Present and Lifetime (K-SADS) Version Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5). Results: We found that 17% of participants met diagnostic criteria for ODD on the K-SADS, whereas 24% exhibited subclinical symptoms. Results also suggest good specificity of Swanson, Nolan, and Pelham-IV Rating Scale (SNAP-IV), Conners' Parent Rating Scales Long Version (CPRS) and Child Behavior Checklist (CBCL) in detecting ODD symptoms. The investigation of the agreement in the prevalence rates of clinical and subclinical symptoms of ODD between K-SADS and the parent-report questionnaires indicated CPRS as the parent-report questionnaire with the best agreement with K-SADS. Discussion: This study provides support for the use of parent-report questionnaires to assess ODD symptoms in children and adolescents with DS by evaluating their levels of agreement with a semi-structured psychopathological interview. In particular, our results suggest that CPRS could be considered a suitable screening tool for ODD clinical and subclinical symptoms in youth with DS.

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Down syndrome (DS) is caused by trisomy of chromosome 21 and it is the most common genetic cause of intellectual disability (ID) in humans. Subjects with DS show a typical phenotype marked by facial dysmorphisms and ID. Partial trisomy 21 (PT21) is a rare genotype characterized by the duplication of a delimited chromosome 21 (Hsa21) portion and it may or may not be associated with DS diagnosis. The highly restricted Down syndrome critical region (HR-DSCR) is a region of Hsa21 present in three copies in all individuals with PT21 and a diagnosis of DS. This region, located on distal 21q22.13, is 34 kbp long and does not include characterized genes. The HR-DSCR is annotated as an intergenic region between KCNJ6-201 transcript encoding for potassium inwardly rectifying channel subfamily J member 6 and DSCR4-201 transcript encoding Down syndrome critical region 4. Two transcripts recently identified by massive RNA-sequencing (RNA-Seq) and automatically annotated on Ensembl database reveal that the HR-DSCR seems to be partially crossed by KCNJ6-202 and DSCR4-202 isoforms. KCNJ6-202 shares the coding sequence with KCNJ6-201 which is involved in many physiological processes, including heart rate in cardiac cells and circuit activity in neuronal cells. DSCR4-202 transcript has the first two exons in common with DSCR4-201, the only experimentally verified gene uniquely present in Hominidae. In this study, we performed in silico and in vitro analyses of the HR-DSCR. Bioinformatic data, obtained using Sequence Read Archive (SRA) and SRA-BLAST software, were confirmed by Reverse Transcription-Polymerase Chain Reaction (RT-PCR) and Sanger sequencing on a panel of human tissues. Our data demonstrate that the HR-DSCR cannot be defined as an intergenic region. Further studies are needed to investigate the functional role of the new transcripts, likely involved in DS phenotypes.

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Individuals with Down syndrome are genetically predisposed to developing acute megakaryoblastic leukemia. This myeloid leukemia associated with Down syndrome (ML-DS) demonstrates a model of step-wise leukemogenesis with perturbed hematopoiesis already presenting in utero, facilitating the acquisition of additional driver mutations such as truncating GATA1 variants, which are pathognomonic to the disease. Consequently, the affected individuals suffer from a transient abnormal myelopoiesis (TAM)-a pre-leukemic state preceding the progression to ML-DS. In our review, we focus on the molecular mechanisms of the different steps of clonal evolution in Down syndrome leukemogenesis, and aim to provide a comprehensive view on the complex interplay between gene dosage imbalances, GATA1 mutations and somatic mutations affecting JAK-STAT signaling, the cohesin complex and epigenetic regulators.

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This review will address the place of innovative, non-chemotherapy, non-CAR-T targeted therapies in the treatment of Acute Lymphoblastic Leukaemia (ALL), focusing on their use in the hematopoietic stem cell transplant (HSCT) context. The focus will be on the agent with the most experience to date, namely the bispecific T-cell engater (BiTE) blinatumomab, but references to antibody-drug conjugates (ADCs) such as inotuzumab ozogamicin and monoclonal antibodies such as daratumamab will be made as well. Specific issues to be addressed include: (1) The use of these agents to reduce measurable residual disease (MRD) prior to HSCT and their potential for improved transplant outcomes due to reduced toxicity compared to traditional chemotherapy salvage, as well as potentially increased toxicity with HSCT with particular agents; (2) the appropriate sequencing of innovative therapies, i.e., when to use BiTEs or antibodies versus CARs pre- and/or post-HSCT; this will include also the potential for impact on response of one group of agents on response to the other; (3) the role of these agents particularly in the post-HSCT relapse setting, or as maintenance to prevent relapse in this setting; (4) special populations in which these agents may substitute for traditional chemotherapy during induction or consolidation in patients with predisposing factors for toxicity with traditional therapy (e.g., Trisomy 21, infants), or those who develop infectious complications precluding delivery of full standard-of-care (SOC) chemotherapy during induction/consolidation (e.g., fungal infections); (5) the evidence we have to date regarding the potential for substitution of blinatumomab for some of the standard chemotherapy agents used pre-HSCT in patients without the above risk factors for toxicity, but with high risk disease going into transplant, in an attempt to decrease current rates of transplant-related mortality as well as morbidity; (6) the unique toxicity profile of these agents and concerns regarding particular side effects in the HSCT context. The manuscript will include both the data we have to date regarding the above issues, ongoing studies that are trying to explore them, and suggestions for future studies to further refine our knowledge base.

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Background: We aimed to assess the clinical application of noninvasive prenatal screening (NIPS) based on second-trimester ultrasonographic soft markers (USMs) in low-risk pregnant women. Methods: Data of pregnant women between April 2015 and December 2019 were retrospectively analyzed. Pregnant women [age at expected date of confinement (EDC) of <35 years; low risks for trisomy 21 (T21) and trisomy 18 (T18) based on maternal serum screening; presenting second-trimester USMs (7 types)] who successfully underwent NIPS and had available follow-up information were included in our study. Cases with positive NIPS results were prenatally diagnosed. All patients were followed up for 6 months to 2 years after NIPS, and their clinical outcomes were obtained. Subgroup analyses were performed according to the different USMs. Results: NIPS suggested that among a total of 10,023 cases, 37 (0.37%) were at high risk of aneuploidy, including 4 T21, 6 trisomy 13 (T13), and 27 sex chromosome abnormalities (SCA). Ten cases with aneuploidy (0.10%) were confirmed by prenatal diagnosis, consisting of two T21 and eight SCA. The eight fetuses with SCA consisted of one monosomy X, two XXY, one XXXY, one XXX, one XYY, and two mosaicisms. T21 was detected in one fetus with absent or hypoplastic nasal bone and one fetus with echogenic intracardiac focus (EICF). SCA was detected in five fetuses with EICF, two fetuses with multiple soft markers, and one fetus with echogenic bowel. The positive rate of chromosomal aneuploidy was significantly higher in fetuses with absent or hypoplastic nasal bone (6.25 vs. 0.10%, p = 0.017), echogenic bowel (3.7 vs. 0.10%, p = 0.029), and multiple soft markers (0.678 vs. 0.10%, p = 0.045) than in the total fetuses. The positive predictive values (PPVs) of NIPS in these three groups were 100%, 50%, and 100%, respectively. EICF accounted for 93.25% (9,346/10,023) of the study population, whereas the PPV of NIPS was only 20%. Conclusion: NIPS is an advanced screening test for low-risk pregnant women. In the 10,023 pregnant women sampled, SCA were more common than autosomal trisomy, and EICF was the most frequent USM but the least predictive aneuploidy. Further aneuploidy evaluation is suggested for low-risk pregnant women whose ultrasound indicates absent or hypoplastic nasal bone, echogenic bowel, or multiple soft markers. NIPS can serve as a second-line complementary screening for these women.

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El síndrome de Down es causado por la presencia de una tercera copia del cromosoma 21 y fue descrito por primera vez en 1838 por Jean-Etienne-Dominique, y más tarde por John Langdon Haydon Down en 1866, mientras trabajaba como superintendente médico en el Asilo Real de Earlswood. Desde ese momento, la comunidad científica puso grandes esfuerzos en tratar de elucidar diversos aspectos que influyen en la naturaleza de esta condición, y que determinan su incidencia y factores de riesgo. De igual manera, se ha puesto interés en los genes involucrados en esta enfermedad, la relación genotipo-fenotipo, la expresión del fenotipo, la variabilidad del material genético y las consecuencias transcripcionales que se producen al tener una tercera copia, ya sea parcial o total, del cromosoma 21. Además, se han invertido esfuerzos en identificar biomarcadores y en diseñar metodologías de diagnóstico prenatal no invasivo que sean altamente eficientes para un mejor diagnóstico del síndrome de Down, y así reducir su impacto negativo en las madres gestantes, al proveerlas de información neutral y precisa acerca de vivir con un hijo con síndrome de Down, y darles autonomía en la decisión de la continuación de su embarazo

Down syndrome is caused by the presence of a third copy of chromosome 21 and was first described by Jean-Etienne-Dominique in 1838, and later by John Langdon Haydon Down in 1866, while working as a medical superintendent in the Royal Earlswood Asylum. Since, the scientific community has placed great efforts in trying to elucidate different influencing features in the nature of this condition that determine their incidence and risk factors. In addition, especial attention has been given to the genes involved in this disease, the genotype-phenotype relationship, the expression of the phenotype, the variability of the genetic material and the transcriptional consequences that are produced by having a third copy, either partial or total, of chromosome 21. Additionally, efforts have been invested in identifying biomarkers and designing noninvasive prenatal methodologies that are highly efficient for a better diagnosis of Down syndrome, in order to reduce its negative impact in pregnant mothers, by providing them with neutral and accurate information about life with a child with Down syndrome, as well as providing the autonomy in the decision to continue their pregnancy

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Congenital myeloproliferative disorders and transient leukemic disorders have been described in the perinatal period in infants with trisomy 21 (Down syndrome). We report a novel case of a neonate with trisomy 21 with GATA1-mutated congenital myeloproliferative disorder complicated by placental fetal thrombotic vasculopathy featuring chorionic vessel leukemic thrombi, fetal circulation vascular injuries, and large aggregates of avascular villi. These thrombotic and vasculopathic changes within the placenta are likely a reflection of the hypercoagulable state caused by the myeloproliferative disorder. Placental fetal thrombotic vasculopathy is associated with adverse outcomes for the infant, and should be documented during formal pathological examination of the placenta.

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