Down Syndrome Patients Research Articles

Hidradenitis suppurativa and Down syndrome: A systematic review and meta-analysis.

Hidradenitis suppurativa (HS), characterized by inflammatory nodules, sinus tracts, and abscesses, has been linked to several factors, including immune dysfunction and obesity, which are thought to contribute to its development. Several follicular disorders have also been associated with Down syndrome (DS), a common chromosomal disorder, including HS, although studies on this topic are limited. To characterize HS in Down syndrome patients and to further examine the association between HS and DS compared to HS patients without DS. We systematically searched MEDLINE, Embase, Web of Science, and CENTRAL electronic databases from their dates of conception to February 2020. Random-effects meta-analyses were performed analyzing (a) HS characteristics between DS and non-DS participants, and (b) prevalence or association between HS and DS compared to non-DS individuals. Twelve studies were included in this systematic review, with a total of 358 participants presenting with both HS and DS. Pooled analysis of mean differences between DS and non-DS participants presenting with HS found a significantly younger age of HS symptom onset for DS patients (-6.24; 95% CI, -10.01--2.24). A meta-analysis examining the association between HS and DS found a significantly increased likelihood of HS in DS patients (OR 9.61; 95% CI, 5.70-16.20). Our findings suggest an association between HS and DS, with DS patients suffering from an earlier onset of HS symptoms compared to non-DS patients.

The overlap between Alzheimer's disease and epilepsy uncovered by transcriptome sequencing

The overlap between Alzheimer's disease and epilepsy uncovered by transcriptome sequencing

Evaluation of biochemical and hematological parameters in adults with Down syndrome

Down syndrome (DS) is the most common worldwide cause of intellectual disability of genetic origin and the most common chromosomal disorder affecting live-born infants. In addition to intellectual disability, individuals with DS have other comorbidities and complex medical conditions. The increase in the life expectancy of patients with DS requires expanding the knowledge about their clinical characteristics and related laboratory parameters. Several studies exploring laboratory tests in DS patients exist, but their focus is limited to specific areas of metabolism. Therefore, our main goal was to describe the biochemical and hematological findings in a DS cohort and to compare the values to those of a control population. A total of 248 DS individuals and 84 control subjects were enrolled. DS individuals had a higher frequency of several clinical conditions compared to control individuals and presented with significant differences with respect to the controls in both biochemical and hematological parameters. We found age- and sex-related differences in several of the parameters. A good understanding of the differences in our cohort might be of aid in the clinical follow-up of adults with DS, especially considering that the lifespan of DS individuals may reach 60 years of age in developed countries.

Chronic PERK induction promotes Alzheimer-like neuropathology in Down syndrome: Insights for therapeutic intervention.

A major challenge in neurobiology is the identification of the mechanisms by which protein misfolding leads to cellular toxicity. Many neurodegenerative disorders, in which aberrant protein conformers aggregate into pathological inclusions, present the chronic activation of the PERK branch of the unfolded protein response. The adaptive effects of the PERK pathway include reduction of translation by transient inhibition of eIF2α and antioxidant protein production via induction of Nrf2 transcription factor. In contrast, PERK prolonged activation leads to sustained reduction in protein synthesis and induction of cell death pathways. To further investigate the role of the PERK pathway in neurodegenerative disorders, we focused on Down syndrome (DS), in which aging confers a high risk of Alzheimer disease (AD). By investigating human DS frontal cortices, we found early and sustained PERK activation associated with the induction of eIF2α and ATF4 downstream signals. We also observed that the Nrf2 response is uncoupled from PERK and its antioxidant effects are repressed in a mechanism implicating the transcription repressor Bach1. The pharmacological inhibition of PERK in DS mice reduced eIF2α-related translational repression and promoted Nrf2 nuclear translocation, favoring the rescue of Nrf2/Bach1 imbalance. The further analysis of peripheral cells from living DS individuals provided strong support of the pathological link between PERK and trisomy 21. Our results suggest that failure to regulate the PERK pathway is a peculiar characteristic of DS pathology and it may represent an essential step to promote cellular dysfunction, which actively contributes in the brain to the early development of AD.

Objective evaluation of corneal and lens densitometry in children with Down syndrome

The goal of this study was to compare anterior segment topographic measurements and densitometry measurements of the cornea and lens of patients with Down syndrome (DS) with those of healthy individuals. Forty patients with DS (study group) and 43 healthy subjects (control group) were enrolled in this prospective study. Topographic measurements, including central corneal thickness (CCT), corneal volume (CV), anterior chamber depth, corneal densitometry (CD) and lens densitometry (LD) values, of the right eye of each participant were obtained. The CCT and CV values were significantly lower in the study group compared to those in the control group. The mean LD-horizontal, LD-vertical, LD-areal, three dimensional (3D), peak and CD values were higher in the patients with DS (5.90±0.7, 6.01±0.7, 5.61±0.54, 9.70±2.1, 20.94±7.53 and 15.61±1.34, respectively) than in the healthy control subjects (5.72±0.65, 5.83±0.60, 5.56±0.75, 8.63±1.83, 17.29±5.40 and 14.3±1.03, respectively) (LD-horizontal P=0.144, LD-vertical P=0.184, LD-areal P=0.743, 3D P=0.033, peak P=0.029 and CD P=0.001). The DS patients had higher CD and LD values. Additionally, the mean CCT and CV values in the DS group were less than those in the control group.

IPSC-derived progenitor stromal cells provide new insights into aberrant musculoskeletal development and resistance to cancer in down syndrome

Down syndrome (DS) is a congenital disorder caused by trisomy 21 (T21). It is associated with cognitive impairment, muscle hypotonia, heart defects, and other clinical anomalies. At the same time, individuals with Down syndrome have lower prevalence of solid tumor formation. To gain new insights into aberrant DS development during early stages of mesoderm formation and its possible connection to lower solid tumor prevalence, we developed the first model of two types of DS iPSC-derived stromal cells. Utilizing bioinformatic and functional analyses, we identified over 100 genes with coordinated expression among mesodermal and endothelial cell types. The most significantly down-regulated processes in DS mesodermal progenitors were associated with decreased stromal progenitor performance related to connective tissue organization as well as muscle development and functionality. The differentially expressed genes included cytoskeleton-related genes (actin and myosin), ECM genes (Collagens, Galectin-1, Fibronectin, Heparan Sulfate, LOX, FAK1), cell cycle genes (USP16, S1P complexes), and DNA damage repair genes. For DS endothelial cells, our analysis revealed most down-regulated genes associated with cellular response to external stimuli, cell migration, and immune response (inflammation-based). Together with functional assays, these results suggest an impairment in mesodermal development capacity during early stages, which likely translates into connective tissue impairment in DS patients. We further determined that, despite differences in functional processes and characteristics, a significant number of differentially regulated genes involved in tumorigenesis were expressed in a highly coordinated manner across endothelial and mesodermal cells. These findings strongly suggest that microRNAs (miR-24-4, miR-21), cytoskeleton remodeling, response to stimuli, and inflammation can impact resistance to tumorigenesis in DS patients. Furthermore, we also show that endothelial cell functionality is impaired, and when combined with angiogenic inhibition, it can provide another mechanism for decreased solid tumor development. We propose that the same processes, which specify the basis of connective tissue impairment observed in DS patients, potentially impart a resistance to cancer by hindering tumor progression and metastasis. We further establish that cancer-related genes on Chromosome 21 are up-regulated, while genome-wide cancer-related genes are down-regulated. These results suggest that trisomy 21 induces a modified regulation and compensation of many biochemical pathways across the genome. Such downstream interactions may contribute toward promoting tumor resistant mechanisms.

Antioxidants in Down Syndrome: From Preclinical Studies to Clinical Trials.

There is currently no effective pharmacological therapy to improve the cognitive dysfunction of individuals with Down syndrome (DS). Due to the overexpression of several chromosome 21 genes, cellular and systemic oxidative stress (OS) is one of the most important neuropathological processes that contributes to the cognitive deficits and multiple neuronal alterations in DS. In this condition, OS is an early event that negatively affects brain development, which is also aggravated in later life stages, contributing to neurodegeneration, accelerated aging, and the development of Alzheimer’s disease neuropathology. Thus, therapeutic interventions that reduce OS have been proposed as a promising strategy to avoid neurodegeneration and to improve cognition in DS patients. Several antioxidant molecules have been proven to be effective in preclinical studies; however, clinical trials have failed to show evidence of the efficacy of different antioxidants to improve cognitive deficits in individuals with DS. In this review we summarize preclinical studies of cell cultures and mouse models, as well as clinical studies in which the effect of therapies which reduce oxidative stress and mitochondrial alterations on the cognitive dysfunction associated with DS have been assessed.

Down’s Syndrome and COVID-19: Risk or Protection Factor against Infection?

Down syndrome (DS) is the most common genetic cause of learning difficulties and intellectual disabilities. DS patients often present with several congenital defects and chronic diseases, including immunity disorders. Elevated levels of pro-inflammatory cytokines such as interleukin (IL) -6 and tumor necrosis factor alpha (TNF-α) have been seen, which appear to vary with age. At birth, patients present with combined immunodeficiency, with frequent infections that decrease with age. Furthermore, high levels of IL-4 and IL-10 with anti-inflammatory properties and low levels of IL-6 and TNF-α are described in children. The immune system is believed to play or play an essential role in SARS-CoV-2 pathogenesis, and it has been associated with elevated levels of pro-inflammatory cytokines and an exaggerated cytokine release syndrome (CRS) that may eventually trigger a severe situation called cytokine storm. On the other hand, genetic features seem to be involved in the predisposition to illness and its severity. Overexpression of DSCR1 and ZAKI-4 inhibits the translocation of activated T-lymphocyte nuclear factor (NF-AT) to the nucleus, a main step in the inflammatory responsiveness. We discuss here, the possible role of immunology and genetic features of DS in the infection and prognosis in COVID-19.

Three Copies of Four Interferon Receptor Genes Underlie a Mild Type I Interferonopathy in Down Syndrome.

Down syndrome (DS) is characterized by the occurrence of three copies of human chromosome 21 (HSA21). HSA21 contains a cluster of four interferon receptor (IFN-R) genes: IFNAR1, IFNAR2, IFNGR2, and IL10RB. DS patients often develop mucocutaneous infections and autoimmune diseases, mimicking patients with heterozygous gain-of-function (GOF) STAT1 mutations, which enhance cellular responses to three types of interferon (IFN). A gene dosage effect at these four loci may contribute to the infectious and autoimmune manifestations observed in individuals with DS. We report high levels of IFN-αR1, IFN-αR2, and IFN-γR2 expression on the surface of monocytes and EBV-transformed-B (EBV-B) cells from studying 45 DS patients. Total and phosphorylated STAT1 (STAT1 and pSTAT1) levels were constitutively high in unstimulated and IFN-α- and IFN-γ-stimulated monocytes from DS patients but lower than those in patients with GOF STAT1 mutations. Following stimulation with IFN-α or -γ, but not with IL-6 or IL-21, pSTAT1 and IFN-γ activation factor (GAF) DNA-binding activities were significantly higher in the EBV-B cells of DS patients than in controls. These responses resemble the dysregulated responses observed in patients with STAT1 GOF mutations. Concentrations of plasma type I IFNs were high in 12% of the DS patients tested (1.8% in the healthy controls). Levels of type I IFNs, IFN-Rs, and STAT1 were similar in DS patients with and without recurrent skin infections. We performed a genome-wide transcriptomic analysis based on principal component analysis and interferon modules on circulating monocytes. We found that DS monocytes had levels of both IFN-α- and IFN-γ-inducible ISGs intermediate to those of monocytes from healthy controls and from patients with GOF STAT1 mutations. Unlike patients with GOF STAT1 mutations, patients with DS had normal circulating Th17 counts and a high proportion of terminally differentiated CD8+ T cells with low levels of STAT1 expression. We conclude a mild interferonopathy in Down syndrome leads to an incomplete penetrance at both cellular and clinical level, which is not correlate with recurrent skin bacterial or fungal infections. The constitutive upregulation of type I and type II IFN-R, at least in monocytes of DS patients, may contribute to the autoimmune diseases observed in these individuals.

Differential levels of Neurofilament Light protein in cerebrospinal fluid in patients with a wide range of neurodegenerative disorders

Cerebrospinal fluid (CSF) biomarkers are useful in the diagnosis and the prediction of progression of several neurodegenerative diseases. Among them, CSF neurofilament light (NfL) protein has particular interest, as its levels reflect neuroaxonal degeneration, a common feature in various neurodegenerative diseases. In the present study, we analyzed NfL levels in the CSF of 535 participants of the SPIN (Sant Pau Initiative on Neurodegeneration) cohort including cognitively normal participants, patients with Alzheimer disease (AD), Down syndrome (DS), frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), dementia with Lewy bodies (DLB), progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS). We evaluated the differences in CSF NfL accross groups and its association with other CSF biomarkers and with cognitive scales. All neurogenerative diseases showed increased levels of CSF NfL, with the highest levels in patients with ALS, FTD, CBS and PSP. Furthermore, we found an association of CSF NfL levels with cognitive impairment in patients within the AD and FTD spectrum and with AD pathology in DLB and DS patients. These results have implications for the use of NfL as a marker in neurodegenerative diseases.

Chronic myeloid leukaemia with pulmonary leucostasis in a young Down syndrome patient

We reported a rare case of chronic myeloid leukaemia (CML) complicated with pulmonary leucostasis in an 11-year-old Down syndrome (DS) patient who presented with respiratory distress. His peripheral blood investigation showed features of CML with 17% circulating blast, with immunophenotyping showing positivity towards myeloid markers. Peripheral blood polymerase chain reaction for BCR–ABL fusion transcripts was positive, and cytogenetic studies showed Ph chromosome with trisomy 21. Despite cytoreduction therapy with hydroxyurea and leukapheresis, the patient succumbed due to shock, with multiple organ failure. Our case highlights the need for early detection and rapid referral for aggressive treatment in DS patients with CML, as the combination is associated with a poor outcome.

0879 Outcomes of Adenotonsillectomy in Children with Down Syndrome and Obstructive Sleep Apnea

Abstract Introduction Obstructive sleep apnea (OSA) is highly prevalent in children with Down Syndrome (DS). The aim of this study was to assess the effectiveness of adenotonsillectomy (T&A) on polysomnographic parameters of children with DS. Methods Retrospective chart review of children with DS who underwent T&A between 2012-2019 was performed. Preoperative OSA severity was categorized by obstructive apnea-hypopnea index (OAHI): mild = 1-4.9 events/h; moderate = 5-9.9 events/h; severe ≥ 10 events/h. Results We identified 43 DS children with pre and post T&A polysomnographic data in a population of 162 DS patients. A total of 25 were male, mean age 5.1 years (± 3.8 years) and 56% Caucasians. Preoperative data showed 19% mild OSA, 30% moderate and 51% severe. Postoperatively, apnea-hypopnea index (AHI) normalized in 9.3%, 37.2% had mild OSA, 18.6% moderate and 34.9% severe. Overall, T&A resulted in significant improvement (p-value <0.05) in mean AHI, (18.51 ± 28.05 vs 11.72 ± 16.43), SaO2 nadir (80.00 ± 14.82 vs 85.51 ± 5.94), sleep efficiency (81.97 ± 11.15 vs 85.9 ± 8.28), arousal index (16.14 ± 10.23 vs 14.45 ± 12.34), and wake after sleep onset (67.19 ± 46.89 vs 50.55 ± 40.83) and no statistical difference (p-value >0.05) in end-tidal carbon dioxide (43.86 ± 9.56 vs 44.17 ± 3.78), Rapid Eye Movement (REM)% (15.86 ± 7.75 vs 15.92 ± 7.41), sleep latency (24.03 ± 34.39 vs 22.55 ± 21.11), and central apnea index (0.86 ± 1.38 vs 0.66 ± 0.82) in pre and post T&A data. There was no statistically significant difference in pre and post T&A polysomnographic parameters between 17 DS and 17 age and gender-matched non-DS control subjects. Conclusion Adenotonsillectomy resulted in improvement in AHI, oxygen desaturation nadir, sleep efficiency, arousal index and wake after sleep onset. However, a significant portion of children with DS continued to have moderate to severe OSA after T&A. Support None.

Bladder bowel dysfunction in children with Down's syndrome.

Bladder Bowel Dysfunction (BBD) has been described in patients with Down's Syndrome (DS). Our aim was to report the incidence, demographics, presentation, complications and management of the bladder in DS patients with BBD. A systematic review was performed using PRISMA guidelines and search terms "{[(trisomy 21) OR down's syndrome]} AND [("non-neurogenic") OR voiding dysfunction]" in the search engines MEDLINE and SCOPUS. We also include a case series from two paediatric urology centres. A total of 38 patients with BBD and DS were included. Mean age was 12years (newborn to 21years), the male:female ratio was 2:1. Functional constipation (90%), recurrent urinary tract infections (38%) and enuresis were common at presentation (56%), while over 56% patients required surgical intervention. Medical treatment and behavioral modification were less successful while intermittent catheterisation did not work. This study reviews the largest cohort of patients with BBD in DS. It is common with serious consequences requiring operative intervention. Usual interventions are unreliable due to poor compliance. Early identification and management protect the renal tract. Regular screening for urogenital anomalies in DS is currently not performed. We recommend a thorough history of bladder function in DS patients to identify these cases early.

Outcomes in children with Down syndrome (DS) and B-lymphoblastic leukemia (B-ALL): A Children’s Oncology Group (COG) report.

10510 Background: Patients with DS and B-ALL experience increased rates of relapse and toxicities. Here, we report results from 4 COG trials (2003-2018). Methods: We analyzed clinical, and outcome data for DS (n = 743) and non-DS (n = 21,703) patients age 1-30 enrolled on standard-risk (SR) trials AALL0331 and AALL0932 and high-risk (HR) trials AALL0232 and AALL1131. Initially, DS-ALL patients on AALL0232/AALL0331 experienced excess mortality, prompting enhanced supportive care and omission of induction anthracycline except for slow responders on AALL1131. Other modifications included: non-random assignment to treatment strata without investigational agents; leucovorin rescue after intrathecal methotrexate (MTX); equal maintenance length for boys and girls; every 12-week maintenance vincristine/steroid pulses; and reduced anthracycline and intravenous MTX for HR patients. Results: Across all 4 trials, DS and non-DS patients did not differ significantly in age, sex, initial WBC, or CNS status. DS-ALL patients had significantly higher end of induction (EOI) minimal residual disease (MRD) vs non-DS patients on both AALL0932 and AALL1131, but the difference persisted at end of consolidation (EOC) only on AALL1131, with fewer EOI MRD+ DS patients achieving EOC MRD < 0.01% (76.1 vs 88.0%, p = 0.001). 5-year EFS and OS were significantly poorer for DS vs non-DS across all trials (EFS 79.6+2.1% vs 86.3+0.3%, p < 0.0001; OS 86.5+1.8% vs 93.1+0.2%, p < 0.0001), as well as on each individual trial. In Cox regression analysis for all DS patients, inferior EFS was associated with several known risk factors (age > 10, EOI MRD >0.01%) but not with cytogenetics or CRLF2 status Induction death was more frequent in DS patients (3.4% vs 0.8%, p < 0.0001) as was death in remission (4.8+0.8% vs 1.8+0.1%, p < 0.0001). For death in remission, the increased frequency occurred pre-maintenance and in patients taken off protocol therapy, but not during maintenance, in contrast to prior reports. Grade >3 mucositis, infections, and hyperglycemia were significantly more frequent in DS patients on all trials. Grade >3 seizures were significantly more frequent in DS patients on HR but not SR trials (4.1% vs 1.7%. p = 0.001) and occurred in all phases pre-maintenance. Conclusions: Patients with DS and B-ALL continue to have inferior outcomes compared to non-DS, with increased relapse and toxicities. Less toxic approaches such as immunotherapies and targeted therapies hold promise to improve outcomes in both these areas.

Differences in morbidity and mortality in Down syndrome are related to the type of congenital heart defect.

Morbidity and mortality in Down syndrome (DS) are mainly related to congenital heart defects (CHDs). While CHDs with high prevalence in DS (typical CHDs), such as endocardial cushion defects, have been extensively described, little is known about the impact of less common CHDs (atypical CHDs), such as aortic coarctation and univentricular hearts. In our single-center study, we analyzed, in observational, retrospective manner, data regarding cardiac features, surgical management, and outcomes of a cohort of DS patients. Literature review was performed to investigate previously reported studies on atypical CHDs in DS. Patients with CHDs were subclassified as having typical or atypical CHDs. Statistical analysis was performed for comparison between the groups. The study population encompassed 859 DS patients, 72.2% with CHDs, of which 4.7% were atypical. Statistical analysis showed a significant excess in multiple surgeries, all-cause mortality and cardiac mortality in patients with atypical CHDs (p = .0067, p = .0038, p = .0001, respectively). According to the Kaplan-Meier method, survival at 10 and 40 years was significantly higher in typical CHDs (99 and 98% vs. 91 and 84%, log rank <0.05). Among atypical CHDs, it seems that particularly multiple complex defects in univentricular physiology associate with a worse outcome. This may be due to the surgical difficulty in managing univentricular hearts with multiple defects concurring to the clinical picture or to the severity of associated defects themselves. Further studies need to address this specific issue, also considering the higher pulmonary pressures, infective complications, and potential comorbidities in DS patients.

Regulation of Human Organic Cation Transporter 3 (hOCT3) by the Dual‐Specifity Tyrosine‐(Y)‐Phosphorylation Regulated Kinase (DYRK1A)

hOCT3, a transmembrane protein with broad tissue distribution, is involved in the low‐affinity, high‐capacity transport of monoamine substrates across the cell membrane. In mice OCT3 is important for cerebral monoaminergic neurotransmission and for the effects of monoamines on behavior. The molecular regulation of hOCT3, however, is unknown.In this study, we have identified the dual‐specificity tyrosine‐(Y)‐phosphorylation regulated kinase 1A (DYRK1A) as a key interaction partner of hOCT3 using a membrane‐based Split‐Ubiquitin‐Yeast‐Two‐Hybrid technique, and pull‐down experiments in hOCT3 and DYRK1A transfected human embryonic kidney (HEK) cells. In these cells, DYRK1A overexpression resulted in hOCT3 phosphorylation at the serines 3 and 537 as determined by phosphoproteomic analysis, and in a significant inhibition of the transport of 4‐4‐dimethylamino‐styryl‐N‐methylpyridinium (ASP+), a fluorescent hOCT3 substrate. DYRK1A overexpression reduced the maximum transport velocity (Vmax) of hOCT3, without changing its affinity for ASP+. The hOCT3 transporter function was rescued by inhibition of DYRK1A with 100 nM harmine. In the seminoma cell line Tcam‐2, which endogenously expresses hOCT3 and DYRK1A, harmine treatment resulted in 1) a significant increased hOCT3 expression in the plasma membrane, as determined by biotinylation experiments; 2) an increase of ASP+ uptake; and 3) a decrease of hOCT3/DYRK1A co‐localization as determined by confocal microscopy. Moreover, in Tcam2 cells, phosphatase activation by 4 h incubation with 10 μM ceramide induced a significant increase of ASP+ uptake.Taken together, these data show that hOCT3 is regulated by DYRK1A via interaction, phosphorylation and change of intracellular distribution. The gene coding for the DYRK1A is localized in the Down syndrome (DS) critical region of chromosome 21 and is a strong candidate gene for DS‐associated mental retardation. Since hOCT3 functions as neurotransmitter reuptake transporter in the brain, we speculate that its inhibition by DYRK1A results in an impaired reuptake of neurotransmitters, and therefore an impoverishment of brain neurotransmitters content. This mechanism may be one of the molecular causes of mental retardation and susceptibility to Alzheimer diseases in DS patients.Support or Funding InformationDeutsche Forschungsgemeinschaft CI 107/11.1

Prospective evaluation of autoimmune and non-autoimmune subclinical hypothyroidism in Down syndrome children.

To evaluate the prevalence and natural course of autoimmune and non-autoimmune subclinical hypothyroidism (SH) in Down syndrome (DS) children and adolescents. Prospective multicenter study. For the study, 101 DS patients with SH (TSH 5-10 mIU/L; FT4 12-22 pmol/L), aged 2-17 years at SH diagnosis were enrolled. Annual monitoring of TSH, FT4, BMI, height, and L-thyroxine dose was recorded for 5 years. Thyroid autoimmunity was tested at diagnosis and at the end of follow-up. Thirty-seven out of 101 patients displayed autoantibody positivity (group A); the remaining 64 were classified as non-autoimmune SH (group B). Group A was characterized by higher median age at SH diagnosis and by more frequent family history of thyroid disease (6.6 vs 4.7 years, P = 0.001; 32.4% vs 7.8%, P = 0.001 respectively), whereas congenital heart defects were more common in group B (65.6% vs 43.2%, P = 0.028). Gender, median BMI (SDS), height (SDS), FT4, and TSH were similar in both groups. At the end of follow-up: 35.1% of group A patients developed overt hypothyroidism (OH) vs 17.2% of group B (P = 0.041); 31.25% of group B vs 10.8% of group A became biochemically euthyroid (P = 0.02); and 37.8% of group A vs 51.5% of group B still had SH condition (P = 0.183). Logistic regression suggested autoimmunity (OR = 3.2) and baseline TSH values (OR = 1.13) as predictive factors of the evolution from SH to OH. In DS children, non-autoimmune SH showed higher prevalence and earlier onset. The risk of thyroid function deterioration over time seems to be influenced by thyroid autoimmunity and higher baseline TSH values.

Spectrum of congenital heart disease in Down syndrome at Faisalabad institute of cardiology: A retrospective study.

Congenital heart disease (CHD) is the most common structural anomaly in Down syndrome children with a variable spectrum all over the world including Pakistan. Objectives: To determine the spectrum of congenital heart disease in Down syndrome at Faisalabad Institute of cardiology (FIC) Faisalabad. Study Design: Retrospective descriptive case series. Setting: Pediatric Cardiology Department of FIC, Faisalabad. Period: From January 2013 to June 2019. Material &amp; Methods: All Consecutive patients of Down syndrome who underwent diagnostic Echocardiography at FIC were enrolled. Those having confirmed diagnosis of CHD were included in the study. Results: Out of 321Down syndrome children77.6% (n=249) had CHD and were enrolled for study. Male were 53.8% (n=134) while 46.2% were female (n=115). Majority of patients were below one year of age (57%, n=142). Acyanotic CHD was seen in 83.1 % of patients (n=207) while 16.9 % (n=42) had cyanotic CHD. Isolated cardiac defects was seen in 73.1% of patients (n=182) while 26.9 % had mixed cardiac lesions (n=67). Ventricular septal defect (VSD) was the most common (22.1%, n=55) solitary lesion followed by 14.5% cases of atrioventricular septal defect (AVSD), PDA (13.3%) and ASD (8.8%). Tetralogy of Fallot (TOF) was seen in 8.4%, AS in 1.2% while TGA, Tricuspid atresia, pulmonary valve stenosis, coarctation and Ebstein anomaly (0.8% each) were less common solitary defects. In mixed cardiac defects VSD with PDA was the most common (n=13, 5.22%) followed by VSD with ASD (n=12, 4.81%) and VSD with RVOTO (n=8, 3.21%). In AVSD cases, RVOTO was present in 2.81% (n=7), PDA with ASD was seen in 2% cases (n=5) while CcTGA, DORV, Pulmonary atresia were least common. Pulmonary Hypertension was present in 54.2% cases of left to right shunt lesions. Conclusion: Incidence of CHD in referred cases of Down syndrome is high (77.6%) at our setup. Acyanotic congenital heart defects are more common. VSD is the most common acyanotic CHD followed by AVSD while TOF is the most common cyanotic CHD.

Physical Fitness and Health-Related Physical Activity Programs in People With Down Syndrome: A Systematic Review

Objective: Down Syndrome (DS) is the most common genetic disease in people with intellectual disability, with a prevalence of 1 in 800-1000 live births. Youth and adolescents with DS are a unique population in terms of health-related physical fitness factors. Methods: In this review study, to investigate the physical fitness factors and physical activity programs for youth and adolescents with DS, a search was conducted in international and national databases such as EBSCO, Medline, PubMed, Elsevier, Google Scholar and SID among studies conducted during 1996-2016 using following keywords in Persian and English: Physical fitness, physical activity, Down syndrome, rehabilitation, intellectual disability, muscular strength, muscular endurance, aerobic fitness, balance, agility and flexibility. Results: Initial search yielded 130 articles. After removing duplicates, 35 were remained for the review. The studies indicated lower cardiorespiratory capacity and physical fitness in people with DS than in their normal peers in strength, endurance, balance and agility as well as increased subcutaneous fat and body fat distribution. Conclusion: Adolescents and youth with DS have low cardiovascular and muscular capacity and physical fitness, overweight/obesity, and reduces health-related physical activities. Future studies should focus on strength testing and training protocols, methods for determining physical activity levels, and practical interventions to increase physical activities in DS patients.

Down Syndrome Reduces the Sedative Effect of Midazolam in Pediatric Cardiovascular Surgical Patients

Down syndrome (DS) is frequently comorbid with congenital heart disease and has recently been shown to reduce the sedative effect of benzodiazepine (BDZ)-class anesthesia but this effect in a clinical setting has not been studied. Therefore, this study compared midazolam sedation after heart surgery in DS and normal children. We retrospectively reviewed patient records in our pediatric intensive care unit (PICU) of pediatric cardiovascular operations between March 2015 and March 2018. We selected five days of continuous post-operative data just after termination of muscle relaxants. Midazolam sedation was estimated by Bayesian inference for generalized linear mixed models. We enrolled 104 patients (average age 26 weeks) of which 16 (15%) had DS. DS patients had a high probability of receiving a higher midazolam dosage and dexmedetomidine dosage over the study period (probability = 0.99, probability = 0.97) while depth of sedation was not different in DS patients (probability = 0.35). Multi regression modeling included severity scores and demographic data showed DS decreases midazolam sedation compared with controls (posterior OR = 1.32, 95% CrI = 1.01–1.75). In conclusion, midazolam dosages should be carefully adjusted as DS significantly decreases midazolam sedative effect in pediatric heart surgery patients.