ZBTB21 suppresses CRE-mediated transcription to impair synaptic function in Down syndrome.

Down syndrome (DS) is the most common chromosomal disorder and a major cause of intellectual disability. The genetic etiology of DS is the extra copy of chromosome 21 (HSA21)-encoded genes; however, the contribution of specific HSA21 genes to DS pathogenesis remains largely unknown. Here, we identified ZBTB21, an HSA21-encoded zinc-finger protein, as a transcriptional repressor in the regulation of synaptic function. We found that normalization of the Zbtb21 gene copy number in DS mice corrected deficits in cognitive performance, synaptic function, and gene expression. Moreover, we demonstrated that ZBTB21 binds to canonical cAMP-response element (CRE) DNA and that its binding to CRE could be competitive with CRE-binding factors such as CREB. ZBTB21 represses CRE-dependent gene expression and results in the negative regulation of synaptic plasticity, learning and memory. Together, our results identify ZBTB21 as a CRE-binding protein and repressor in cAMP-dependent gene regulation, contributing to cognitive defects in DS.

Trisomy 21 with Maternally Inherited Balanced Translocation (15q;22q) in a Female Fetus: A Rare Case of Probable Interchromosomal Effect.

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?

Potential efficacy of digital polymerase chain reaction for non-invasive prenatal screening of autosomal aneuploidies: a systematic review and meta-analysis.

BACKGROUND: Digital Polymerase Chain Reaction (dPCR) presents a promising approach for quantifying DNA and analyzing copy number variants, particularly in non-invasive prenatal testing. This method offers a streamlined and time-efficient procedure in contrast to the widely used next-generation sequencing for non-invasive prenatal testing. Studies have reported encouraging results for dPCR in detecting fetal autosomal aneuploidies. Consequently, this systematic review aimed to evaluate the effectiveness of dPCR in screening for trisomy 21, 18, and 13. METHODS: A systematic search was conducted in PubMed, Web of Sciences, and Embase for relevant articles published up to December 30, 2023. The Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) was utilized for the quality assessment of the included articles. Furthermore, a bivariate random-effect regression model was used to conduct a meta-analysis on the utility of dPCR for trisomy 21 screening. RESULTS: A total of 9 articles were included in this review, with all of them assessing the utility of dPCR in trisomy 21 screening, and 2 and 1 studies conducting additional analysis on the screening abilities of dPCR for trisomy 18 and 13, respectively. A bivariate random-effects model calculated pooled sensitivity and specificity with a 95% confidence interval (CI). Meta-analysis of 6 studies comparing trisomy-21 screening with karyotyping demonstrated dPCR's pooled sensitivity of 98% [95% CI: 94 -100] and specificity of 99% [95% CI: 99 -100]. While conducting a meta-analysis for trisomy 13 and 18 proved impractical, reported values for sensitivity and specificity were favorable. CONCLUSIONS: These findings suggest that dPCR holds promise as an effective tool for non-invasive prenatal testing, presenting a less time-consuming and intricate alternative to next-generation sequencing. However, further research is necessary to evaluate dPCR's applicability in clinical settings and to delineate its specific advantages over next-generation sequencing. This study contributes valuable insights into the potential of dPCR for enhancing prenatal screening methodologies. TRIAL REGISTRATION: The protocol of this study was registered in the International Prospective Register of Systematic Reviews (PROSPERO) on 7/3/2024, with a registration code of CRD42024517523.

Giant Urinary Bladder in a Woman with Down Syndrome: A Case Report.

BACKGROUND Non-neurogenic neurogenic bladder involves fluctuating flow rates due to involuntary muscle contractions during voiding in those with normal neurological function. The diagnostic challenge lies in distinguishing between massive urinary bladder distension and ovarian tumors. While various pathologies mimicking ovarian tumors are documented, cases of a massively distended urinary bladder, known as giant urinary bladder, posing as such are notably scarce. CASE REPORT This case report presents the unique clinical scenario of a 31-year-old woman with Down syndrome who was initially misdiagnosed with an ovarian tumor due to progressive abdominal distention, reduced appetite, and weight loss. On presentation, she appeared dehydrated, with an abnormal renal profile. Despite hydration, the renal profile worsened. Initial ultrasound showed a large, uniloculated cystic lesion measuring 11×15 cm in the pelvis. Due to the size of the cyst, which appeared to be ovarian in origin, ovarian tumor was suspected. However, tumor markers were normal. A computed tomography scan subsequently showed a massively distended urinary bladder measuring 11.6×13.6×17.6 cm causing bilateral obstructive uropathy, with moderate hydronephrosis and hydroureter. Needing intermittent catheterization at first, the patient subsequently passed urine on her own following behavioral modification. CONCLUSIONS This rare case of non-neurogenic neurogenic bladder causing a giant urinary bladder in a patient with Down syndrome highlights the importance of an awareness of this condition for effective assessment and patient treatment.

A clinical-translational review of sleep problems in neurodevelopmental disabilities.

Sleep disorders are very common across neurodevelopmental disorders and place a large burden on affected children, adolescents, and their families. Sleep disturbances seem to involve a complex interplay of genetic, neurobiological, and medical/environmental factors in neurodevelopmental disorders. In this review, we discuss animal models of sleep problems and characterize their presence in two single gene disorders, Rett Syndrome, and Angelman Syndrome and two more commonly occurring neurodevelopmental disorders, Down Syndrome, and autism spectrum disorders. We then discuss strategies for novel methods of assessment using wearable sensors more broadly for neurodevelopmental disorders in general, including the importance of analytical validation. An increased understanding of the mechanistic contributions and potential biomarkers of disordered sleep may offer quantifiable targets for interventions that improve overall quality of life for affected individuals and their families.

The use of hearing tests to assess otitis media with effusion in children with Down syndrome.

BACKGROUND: Down syndrome is associated with an increased risk for otitis media with effusion (OME), a childhood condition in which fluid accumulates in the middle ear, potentially leading to hearing loss. The American Academy of Pediatrics Down syndrome guidelines and the American Academy of Otolaryngology - Head and Neck Surgery OME guidelines recommend hearing testing to assess the hearing status of children with Down syndrome diagnosed with OME. METHODS: Through an Institutional Review Board approved retrospective chart review at Children's Mercy, this project assessed how clinical factors affect the frequency in which children with Down syndrome receive hearing testing after diagnosis of OME. The study included data from all children with Down syndrome between 1 and 8 years old diagnosed with OME in the Down syndrome, general pediatrics, and otolaryngology clinics between 2018 and 2020. Demographics and clinical factors, including clinic setting, were collected. RESULTS: Of the 124 patients identified, 91.1 % were diagnosed with OME in the otolaryngology clinic and 33.1 % received hearing testing. While most diagnoses occurred in the otolaryngology clinic, a higher proportion of hearing testing at the time of diagnosis occurred in the Down syndrome clinic. This could be explained by the fact that the Down syndrome clinic is a multidisciplinary clinic, where yearly visits include hearing screening. Bivariate analysis using chi-square or Fisher's tests showed that clinic setting had a significant association (p-value <0.001) with hearing testing. However, logistic regression depicted all clinical factors had an insignificant effect on hearing testing at 5 % significance. CONCLUSION: While results indicate hearing testing is largely not performed to assess OME early in otolaryngology clinics, they may be used to assess intervention efficacy post-diagnosis. Results point to the importance of Down syndrome clinics in early diagnosis of hearing loss leading to timely referrals to otolaryngology clinics which diagnose and manage OME in children with Down syndrome.

Modeling the impact of neuromorphological alterations in Down syndrome on fast neural oscillations.

Cognitive disorders, including Down syndrome (DS), present significant morphological alterations in neuron architectural complexity. However, the relationship between neuromorphological alterations and impaired brain function is not fully understood. To address this gap, we propose a novel computational model that accounts for the observed cell deformations in DS. The model consists of a cross-sectional layer of the mouse motor cortex, composed of 3000 neurons. The network connectivity is obtained by accounting explicitly for two single-neuron morphological parameters: the mean dendritic tree radius and the spine density in excitatory pyramidal cells. We obtained these values by fitting reconstructed neuron data corresponding to three mouse models: wild-type (WT), transgenic (TgDyrk1A), and trisomic (Ts65Dn). Our findings reveal a dynamic interplay between pyramidal and fast-spiking interneurons leading to the emergence of gamma activity (∼40 Hz). In the DS models this gamma activity is diminished, corroborating experimental observations and validating our computational methodology. We further explore the impact of disrupted excitation-inhibition balance by mimicking the reduction recurrent inhibition present in DS. In this case, gamma power exhibits variable responses as a function of the external input to the network. Finally, we perform a numerical exploration of the morphological parameter space, unveiling the direct influence of each structural parameter on gamma frequency and power. Our research demonstrates a clear link between changes in morphology and the disruption of gamma oscillations in DS. This work underscores the potential of computational modeling to elucidate the relationship between neuron architecture and brain function, and ultimately improve our understanding of cognitive disorders.

Emerging adults' emotions toward their siblings with down syndrome.

BACKGROUND: Typically-developing siblings of individuals with Down Syndrome often experience complex emotions towards their sibling. This study explored how social support, personal resources (optimism, sense of coherence [SOC]), and individual variables (sex, religious affiliation, siblings' functionality) may impact emerging adult siblings' emotions toward their sibling with Down Syndrome. METHODS: Participants were 292 siblings of individuals with DS ranging in age from 18-27 (M=21.54, SD=2.50). Participants completed self-report questionnaires exploring optimism, SOC, support, and acceptance. RESULTS: Higher levels of support and optimism were positively associated with positive emotions, and higher SOC with lower levels of negative emotions. Siblings' functionality and religious affiliation interacted with variables to predict emotions. CONCLUSIONS: This study contributes to a greater understanding of how emotions may play a role in sibling relations during the emerging adulthood stage. It also provides unique insight into how religious affiliation may be associated with more positive outcomes for siblings.

An investigation of sleep problems, gastrointestinal symptoms, comorbid psychopathology and challenging behavior in children and adolescents with Down Syndrome.

BACKGROUND: Down syndrome (DS) is one of the most common chromosomal abnormalities, and children with DS have increased risks of receiving diagnoses of specific comorbidities. AIMS: This study aimed to assess the frequencies and relationships between sleep problems, gastrointestinal (GI) symptoms, comorbid psychopathology, and challenging behavior. METHODS AND PROCEDURES: The Children's Sleep Habits Questionnaire, Gastrointestinal Symptom Inventory, Autism Spectrum Disorder-Comorbid for Children, and Behavior Problems Inventory-Short Form were completed by 123 parents of children and adolescents with DS. OUTCOMES AND RESULTS: The frequency of GI symptoms was 74.8 %, with high frequencies also found for: sleep problems (100 %), challenging behavior (100 %), and moderate to severe levels of comorbid psychopathology (tantrum=80 %; repetitive behavior=63 %; avoidant behavior=82 %; worry/depressed=61 %; conduct behavior=100 %; over-eating=100 %; under-eating=100 %). A significant moderate correlation was found between total GI symptoms and self-injurious behavior frequency. Children who presented with abdominal pain engaged in self-injurious behavior more frequently than those with no abdominal pain. CONCLUSIONS AND IMPLICATIONS: Findings indicated a high frequency of sleep problems, comorbid psychopathology, GI symptoms, and challenging behavior and demonstrated a relationship between GI symptoms and self-injurious behavior in children and adolescents with DS. This research illustrated the importance of investigating comorbid conditions in individuals with DS. WHAT THIS PAPER ADDS?: Down Syndrome (DS) is a genetic condition characterized by trisomy 21 and is a leading cause of intellectual disability worldwide. The prevalence of DS is commonly associated with advanced maternal age and is associated with multiple comorbid conditions. The current study aimed to investigate the frequency of and relationship between sleep problems, gastrointestinal symptoms, comorbid psychopathology, and challenging behavior in children and adolescents with DS. High-frequency levels were found for sleep problems (100 %), challenging behavior (100 %), gastrointestinal symptoms (74.8 %), and moderate to severe levels of the different comorbid psychopathologies (tantrum=80 %; repetitive behavior=63 %; avoidant behavior=82 %; worry/depressed=61 %; conduct behavior=100 %; over-eating=100 %; under-eating=100 %). Results indicated a significant difference in self-injurious behavior frequency between individuals who presented with abdominal pain and those who did not. This study is the first to investigate the relationship of multiple comorbid conditions in a sample of children with DS. This paper adds to the literature by demonstrating the frequency of a number of comorbid conditions in children and adolescents with DS. The paper also adds novel findings to the literature by investigating the relationships between comorbid conditions in this population. The findings of this paper highlighted the frequency and comorbidities that exist between gastrointestinal symptoms, sleep problems, comorbid psychopathology, and challenging behavior. Analyses indicated that those who presented with abdominal pain, engaged in self-injurious behavior more frequently. Sleep problems, gastrointestinal symptoms, comorbid psychopathology, and challenging behavior in children and adolescents with Down Syndrome.

Severe myxedema coma and pericardial effusion in a child with Down syndrome: the importance of adherence to levothyroxine therapy.

BACKGROUND: Myxedema coma is a rare, but life-threatening endocrinological emergency. Myxedema is characterized by altered mental status, and is accompanied by hypotension, bradycardia, hypothermia, bradypnea, hyporeflexia, hyponatremia, and hypoglycemia, all stemming from reduced metabolism due to severe hypothyroidism. Additionally, patients may exhibit signs of low cardiac output, edema in the extremities, peripheral circulatory disturbances, shock, and the development of pericardial and pleural effusions, ultimately leading to confusion and coma. We present a successfully treated case of severe myxedema coma with recurrent pericardial effusion and hypotensive shock. This case is characterized by an unusual clinical presentation and required a distinct treatment strategy highlighting its exceptional rarity. CASE: A 2-year-old boy with Down syndrome presented with recurrent pericardial effusion attributed to medication non-adherence. The critically-ill patient, experiencing a severe cardiogenic shock required mechanical ventilation and inotropic infusions in the pediatric intensive care unit. Elevated thyroid stimulating hormone (TSH), and low free T4 (fT4) and free T3 (fT3) levels prompted consideration of myxedema coma. Upon reviewing the patient's medical history, it was ascertained that he had an ongoing diagnosis of primary hypothyroidism, and exhibited non-adherence to the prescribed treatment regimen and failed to attend scheduled outpatient clinic appointments for follow-up assessments. The treatment plan, devised by the pediatric endocrinology team, included the peroral administration of L-thyroxine (L-T4) at a dose of 50 micrograms per day. After beginning regular oral L-T4 treatment, a gradual improvement in the patient's condition was observed. Notably, by the 15th day of oral therapy, the patient had made a full recovery. Contrary to the recommended intravenous treatment for myxedema coma, this patient was successfully treated with oral levothyroxine, due to the unavailability of the parenteral form in Türkiye. CONCLUSIONS: This case report presents an instance of non-adherence to L-T4 therapy, which subsequently progressed to severe myxedema coma. Changes in neurologic status and hemodynamic instability in a patient with a history of hypothyroidism should raise the concern of nonadherence and, though rare, myxedema coma should be in the differential diagnosis.

Down syndrome and postoperative hemodynamics in patients undergoing surgery for congenital cardiac communications.

Although Down syndrome (DS) is considered a risk factor for hemodynamic instabilities (mainly pulmonary hypertension-PH) following surgery for congenital cardiac communications, many DS patients do surprising well postoperatively. We prospectively analyzed perioperative factors for a possible correlation with post-cardiopulmonary bypass (CPB) inflammatory reaction and postoperative PH in pediatric subjects. Sixty patients were enrolled (age 3 to 35 months), 39 of them with DS. Clinical and echocardiographic parameters (anatomical and hemodynamic) were computed preoperatively. Pulmonary and systemic mean arterial pressures (PAP and SAP) were assessed invasively intra and postoperatively. Immediate postoperative PAP/SAP ratio (PAP/SAPIPO) and the behavior of pressure curves were selected as primary outcome. Serum levels of 36 inflammatory proteins were measured by chemiluminescence preoperatively and 4 h post CPB. Of all factors analyzed, peripheral oxygen saturation (O2Sat, bedside assessment) was the only preoperative predictor of PAP/SAPIPO at multivariate analysis (p = 0.007). Respective values in non-DS, DS/O2Sat ≥ 95% and DS/O2Sat < 95% subgroups were 0.34 (0.017), 0.40 (0.027) and 0.45 (0.026), mean (SE), p = 0.004. The difference between non-DS and DS groups regarding postoperative PAP curves (upward shift in DS patients, p = 0.015) became nonsignificant (p = 0.114) after adjustment for preoperative O2Sat. Post-CPB levels of at least 5 cytokines were higher in patients with O2Sat < 95% versus those at or above this level, even within the DS group (p < 0.05). Thus, a baseline O2Sat < 95% representing pathophysiological phenomena in the airways and the distal lung, rather than DS in a broad sense, seems to be associated with post-CPB inflammation and postoperative PH in these patients.

Amyloid-ß peptide signature associated with cerebral amyloid angiopathy in familial Alzheimer's disease with APPdup and Down syndrome.

Alzheimer's disease (AD) is characterized by extracellular amyloid plaques containing amyloid-ß (Aß) peptides, intraneuronal neurofibrillary tangles, extracellular neuropil threads, and dystrophic neurites surrounding plaques composed of hyperphosphorylated tau protein (pTau). Aß can also deposit in blood vessel walls leading to cerebral amyloid angiopathy (CAA). While amyloid plaques in AD brains are constant, CAA varies among cases. The study focuses on differences observed between rare and poorly studied patient groups with APP duplications (APPdup) and Down syndrome (DS) reported to have higher frequencies of elevated CAA levels in comparison to sporadic AD (sAD), most of APP mutations, and controls. We compared Aß and tau pathologies in postmortem brain tissues across cases and Aß peptides using mass spectrometry (MS). We further characterized the spatial distribution of Aß peptides with MS-brain imaging. While intraparenchymal Aß deposits were numerous in sAD, DS with AD (DS-AD) and AD with APP mutations, these were less abundant in APPdup. On the contrary, Aß deposits in the blood vessels were abundant in APPdup and DS-AD while only APPdup cases displayed high Aß deposits in capillaries. Investigation of Aß peptide profiles showed a specific increase in Aßx-37, Aßx-38 and Aßx-40 but not Aßx-42 in APPdup cases and to a lower extent in DS-AD cases. Interestingly, N-truncated Aß2-x peptides were particularly increased in APPdup compared to all other groups. This result was confirmed by MS-imaging of leptomeningeal and parenchymal vessels from an APPdup case, suggesting that CAA is associated with accumulation of shorter Aß peptides truncated both at N- and C-termini in blood vessels. Altogether, this study identified striking differences in the localization and composition of Aß deposits between AD cases, particularly APPdup and DS-AD, both carrying three genomic copies of the APP gene. Detection of specific Aß peptides in CSF or plasma of these patients could improve the diagnosis of CAA and their inclusion in anti-amyloid immunotherapy treatments.

Recurrence of anterior congenital diaphragmatic hernia after laparoscopic repair in children.

PURPOSE: To report our experience with laparoscopic repair of anterior congenital diaphragmatic hernia (CDH) using extracorporeal subcutaneous knot tying and to define recurrence risk factors. METHODS: This retrospective unicentric study included children who underwent laparoscopic repair of anterior CDH without patch, using extracorporeal knot tying of sutures passed through the full thickness of the abdominal wall (2013-2020). A systematic review of the literature with meta-analysis was performed using the MEDLINE database since 2000. RESULTS: Eight children were included (12 months [1-183]; 10.6 kg [3.6-65]). Among the two patients with Down syndrome, one with previous cardiac surgery had a recurrence at 17 months postoperatively. In our systematic review (26 articles), among the 156 patients included, 10 had a recurrence (none with patch). Recurrence was statistically more frequent in patients with Down syndrome (19.4%) than without (2.5%) (p < 0.0001), and when absorbable sutures were used (50%) instead of non-absorbable sutures (5.3%) (p < 0.0001). CONCLUSION: Laparoscopic repair of anterior CDH without patch was a safe and efficient surgical approach in our patients. The use of a non-absorbable prosthetic patch should be specifically discussed in anterior CDH associated with Down syndrome and/or in case of previous cardiac surgery to perform a diaphragmatic tension-free closure.

A multi-center cross-sectional comparison of parent-reported quality of life and bowel function between anorectal malformation and Hirschsprung's disease patients with versus those without Down syndrome.

PURPOSE: Down syndrome (DS) is a common abnormality associated with anorectal malformation (ARM) and Hirschsprung's disease (HD). However, quality of life (QOL) in ARM and HD patients with DS is under-researched. This study compares parent-reported QOL and bowel function in ARM and HD patients with DS to those without. METHODS: Between December 2020 to February 2023, parents of ARM and HD patients with and without DS aged 3-17 years who had undergone surgery > 12 months prior at four tertiary referral centers were recruited. We used the Pediatric Quality of Life Inventory™ (PedsQL™) Generic Core Scales, General Well-Being (GWB) Scale and Family Impact (FI) Module questionnaires, and the Rintala bowel function score (BFS). RESULTS: There were 101 ARM, 9 (8.9%) of whom had DS; and 87 HD, of whom 6 (6.9%) had DS. Parent-reported Core scores in ARM and HD with DS were comparable to those without DS. However, ARM and HD with DS had worse scores in the FI Module and bowel function than those without DS. CONCLUSION: Although parent-reported QOL in ARM and HD with DS is similar to those without DS, family impact and BFS are worse. Our findings are limited by small sample size in proportion of DS patients.

Compromiso inmunológico en pacientes con síndrome de Down. Serie de casos / Immune compromise in patients with Down syndrome. A case series

El síndrome de Down, o trisomía 21, tiene una mortalidad mayor que la población general, debido principalmente a infecciones respiratorias. El objetivo de este trabajo es describir el compromiso inmunológico en una serie de casos de pacientes con síndrome de Down derivados a Inmunología por infecciones recurrentes o por hallazgo patológico de laboratorio, entre el 1 de junio de 2016 y el 31 de mayo de 2022. Se describe el compromiso de la inmunidad en 24 pacientes. Doce pacientes presentaron falla de respuesta a polisacáridos y recibieron quimioprofilaxis antibiótica y/o gammaglobulina sustitutiva. En 3 pacientes, se observó agammaglobulinemia con linfocitos B presentes y se indicó gammaglobulina sustitutiva. En 9 pacientes, se observó linfopenia T y en 1 paciente, compromiso inmune combinado.

Down syndrome, or trisomy 21, has a higher mortality than the general population, mainly due to respiratory tract infections. The objective of this study was to describe immune compromise in a series of cases of patients with Down syndrome referred to the Pediatric Immunology Section due to recurrent infections or pathological laboratory findings between 6/1/2016 and 5/31/2022. Here we describe immune compromise in 24 patients. Twelve patients failed to develop a polysaccharide response and received antibiotic chemoprophylaxis, or gamma globulin replacement therapy. Three patientsdeveloped agammaglobulinemia with presence of B cells and gamma globulin replacement therapy was indicated. Nine patients had T-cell lymphopenia and 1 patient, combined immune compromise.

The Feasibility of an Online Language Program Delivered Through Music and the Impact of Dosage on Vocabulary Outcomes in Young Children With Down Syndrome.

BACKGROUND: Few studies have explored the feasibility of online language interventions for young children with Down syndrome. Additionally, none have manipulated dose frequency or reported on the use of music as a medium through which language and sign can be learned. PURPOSE: The purpose of this study was to (a) examine the feasibility and acceptability of an online language through music intervention for young children (1-3;6 years) with Down syndrome and (b) compare effectiveness at two intervention dose frequencies. METHOD: The study was carried out in two phases using a mixed-methods design. Phase 1: Qualitative data were gathered from parents to examine feasibility when implementing a video-based language intervention. Phase 2: Seventy-six families participated in an online language intervention at home. Effectiveness was examined comparing two groups, randomly assigned to a high and low dose frequency. The Down Syndrome Education (DSE) checklists (combined) were the primary outcome measure. Process data were gathered to determine intervention acceptability in practice and to identify factors that would improve successful future implementation. Acceptability data were analyzed with reference to the theoretical framework of acceptability (Version 2). RESULTS: Forty-three parents completed the Phase 1 scoping questionnaire, five of whom took part in focus groups. Once weekly morning sessions were indicated as the preferred scheduling choice. Phase 2 quantitative data were analyzed using beta regression adjusted for baseline scores and indicated no additional benefit to receiving the higher dose. However, exploratory interaction models suggested that the efficacy of the high-dose intervention was higher (than low-dose intervention) in participants with higher baseline DSE performance. Parents perceived the intervention to be effective and positive for the family. CONCLUSION: The results add to our knowledge of real-world effective online interventions and suggest that a critical minimum language level is required for children with Down syndrome to benefit optimally from a higher intervention dose frequency. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.25979704.

Foot Muscle Exercise: A Novel Approach to Improve Motor Functions in Children with Down Syndrome Having Pes Planus - A Randomized Controlled Trial.

OBJECTIVE: The study aimed to determine the efficacy of foot muscle exercises in children with DS having pes planus. METHODS: Forty-seven subjects randomly assigned to foot muscle exercises (study group) or an arch support insole with one-leg balance exercises (control group), thrice weekly intervention for 12-weeks followed by a home program with residual effect assessed after 24-weeks from baseline. RESULTS: The motor functions were significantly improved in both groups (p = 0.00). A positive residual effect was found in the study group for both parameters. Whilst in the control group it failed to give a positive residual effect for GMFM-88, while PBS yielded positive outcomes. The study group showed significantly better results than the control group in comparison. CONCLUSION: The novel finding suggests that the foot muscle exercise has the potential to improve motor functions in children with Down syndrome and it can be used as an alternative therapeutic approach to the conventional method.

The child who lived: Down syndrome among Neanderthals?

Caregiving for disabled individuals among Neanderthals has been known for a long time, and there is a debate about the implications of this behavior. Some authors believe that caregiving took place between individuals able to reciprocate the favor, while others argue that caregiving was produced by a feeling of compassion related to other highly adaptive prosocial behaviors. The study of children with severe pathologies is particularly interesting, as children have a very limited possibility to reciprocate the assistance. We present the case of a Neanderthal child who suffered from a congenital pathology of the inner ear, probably debilitating, and associated with Down syndrome. This child would have required care for at least 6 years, likely necessitating other group members to assist the mother in childcare.

Variegated overexpression of chromosome 21 genes reveals molecular and immune subtypes of Down syndrome.

Individuals with Down syndrome, the genetic condition caused by trisomy 21, exhibit strong inter-individual variability in terms of developmental phenotypes and diagnosis of co-occurring conditions. The mechanisms underlying this variable developmental and clinical presentation await elucidation. We report an investigation of human chromosome 21 gene overexpression in hundreds of research participants with Down syndrome, which led to the identification of two major subsets of co-expressed genes. Using clustering analyses, we identified three main molecular subtypes of trisomy 21, based on differential overexpression patterns of chromosome 21 genes. We subsequently performed multiomics comparative analyses among subtypes using whole blood transcriptomes, plasma proteomes and metabolomes, and immune cell profiles. These efforts revealed strong heterogeneity in dysregulation of key pathophysiological processes across the three subtypes, underscored by differential multiomics signatures related to inflammation, immunity, cell growth and proliferation, and metabolism. We also observed distinct patterns of immune cell changes across subtypes. These findings provide insights into the molecular heterogeneity of trisomy 21 and lay the foundation for the development of personalized medicine approaches for the clinical management of Down syndrome.

Aortic Valve Thrombus, Stroke, and Endovascular Thrombectomy in a Child With APML and Trisomy 21.

APML, a subtype of acute myeloid leukemia, is highly curable, with cure rates over 90%. Despite its therapeutic success, APML poses elevated bleeding risks due to frequent prior disseminated intravascular coagulation. Less commonly recognized but critical is the thrombotic risk. We document a unique pediatric case: a 13-year-old with trisomy 21 diagnosed with APML had an asymptomatic aortic valve thrombus leading to thromboembolic arterial ischemic stroke. Through endovascular thrombectomy, cerebral circulation was re-established, extracting a fibrin thrombus with APML cells. Neurological recovery was swift. This report underscores the importance of vigilance for thrombotic complications in APML, highlighting the potential severity of overlooked risks.