Down syndrome (DS) is associated with immune dysfunction, which led to higher hospitalization and mortality rates during the COVID-19 pandemic. We previously showed that antibody concentrations were lower in adults with DS after primary SARS-CoV-2 vaccination. However, knowledge on cellular vaccine-induced responses in DS is limited. Here, we investigated the T-cell response induced by SARS-CoV-2 vaccination in adults with DS. We included adults with DS and healthy controls (HC) between 18 and 64 years following primary (mRNA and vector) and booster (mRNA) SARS-CoV-2 vaccination. Using flow cytometry, SARS-CoV-2-specific T cells were analyzed after spike peptide re-stimulation. Additionally, interferon-gamma (IFNγ) production by SARS-CoV-2-specific T cells was measured with an IFNγ release assay (IGRA) after antigen stimulation. We observed major deficits in naive CD4+ and CD8+ T cells in adults with DS as previously described. However, overall there was no difference in the percentage of SARS-CoV-2-specific T cells or IFNγ production by these cells after primary vaccination, albeit with vaccine-specific differences. IFNγ concentrations measured by IGRA after primary vaccination were comparable between DS and HC. Booster vaccination increased SARS-CoV-2-specific T cells in HC but not in DS, while IFNγ release (IGRA) increased to similar concentrations. In conclusion, we show that while functional T-cell responses (IFNγ production) are comparable after primary and booster vaccination, the magnitude (percentage of SARS-CoV-2-specific T cells) may be lower after mRNA vaccination. We previously showed lower antibody concentrations and profound abnormalities in the naive T-cell compartment, warranting further investigation into T-cell-B-cell-interactions after vaccination in adults with DS.Clinical trial registration: NCT05145348 https://www.clinicaltrials.gov/study/NCT05145348?locStr=Netherlands&country=Netherlands&cond=Down%20Syndrome&term=SARS-CoV-2%20Vaccination&rank=1.Start date: 2021-02-03.

The role of CT scans for imaging Down syndrome patients (Radhakrishnan et al., Pediatr Radiol 2014)

Estimated potential bias of the relative risk for a brain tumor among high versus low exposed subjects by failure to adjust for neurofibromatosis type I (NF1)

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

The total uptake of prenatal aneuploidy screening for Down syndrome (DS) is increasing worldwide. As a result of increasing prenatal diagnosis of DS and subsequent termination of pregnancy, livebirth prevalence of DS is decreasing. The aim of this study is to explore the impact of an increasing uptake of prenatal aneuploidy screening on the neonatal mortality and morbidity in DS. This is a retrospective cohort study of 253 neonates with DS born between 2012 and 2018 that were seen at the outpatient clinic of five hospitals in the Netherlands. The medical files were reviewed for maternal and neonatal characteristics and neonatal morbidities. The Dutch national birth registry (Perined) provided mortality numbers of neonates with DS. The results were interpreted in the context of other published studies. Neonatal mortality in DS remained stable, ranging from 1.4 to 3.6%. A congenital heart defect (CHD) was found in 138 of the 251 neonates (55.0%) with atrial septal defect, atrioventricular septal defect, and ventricular septal defect being the most common. The type of CHD in DS did not change over time. Gastro-intestinal defects were present in 22 of the 252 neonates with DS (8.7%), with duodenal atresia as the most reported anomaly. Persistent pulmonary hypertension of the neonate (PPHN) was found in 31 of the 251 infants (12.4%). Conclusions : Although uptake of prenatal aneuploidy screening increased, neonatal mortality and morbidity in DS appears to be stable. An increased incidence of PPHN was found. What is Known: • The total uptake of prenatal aneuploidy screening for Down syndrome is increasing worldwide. • As a result of increasing prenatal diagnosis of Down syndrome and subsequent termination of pregnancy, the livebirth prevalence of Down syndrome is decreasing. What is New: • Although uptake of prenatal aneuploidy screening increased, neonatal mortality and morbidity in Down syndrome appears to be stable. • An increased incidence of persistent pulmonary hypertension of the neonate was found.

The risk of a severe course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in adults with Down syndrome is increased, resulting in an up to 10-fold increase in mortality, in particular in those >40 years of age. After primary SARS-CoV-2 vaccination, the higher risks remain. In this prospective observational cohort study, SARS-CoV-2 spike S1-specific antibody responses after routine SARS-CoV-2 vaccination (BNT162b2, messenger RNA [mRNA]-1273, or ChAdOx1) in adults with Down syndrome and healthy controls were compared. Adults with Down syndrome showed lower antibody concentrations after 2 mRNA vaccinations or after 2 ChAdOx1 vaccinations. After 2 mRNA vaccinations, lower antibody concentrations were seen with increasing age. In this prospective cohort study that included 222 adults with Down syndrome, a significantly lower antibody response was found after SARS-CoV-2 mRNA or vector vaccination compared to healthy controls. After mRNA vaccination, lower antibodies were found with increasing age.

Objective To evaluate if non-invasive prenatal testing (NIPT) affects livebirth (LB) prevalence of Down syndrome (DS) in the Netherlands. Method Data from clinical genetics laboratories and the Working Party on Prenatal Diagnosis and Therapy (2014-2018) and previous published data (1991-2013) were used to assess trends for DS LB prevalence and reduction percentage (the net decrease in DS LBs resulting from selective termination of pregnancies). Statistics Netherlands provided general population data. Results DS LB prevalence increased from 11.6/10,000 in 1991 to 15.9/10,000 in 2002 (regression coefficient 0.246 [95% CI: 0.105-0.388; p = 0.003]). After 2002, LB prevalence decreased to 11.3/10,000 in 2014 and further to 9.9/10,000 in 2018 (regression coefficient 0.234 (95% CI: -0.338 to -0.131; p < 0.001). The reduction percentage increased from 26% in 1991 to 55.2% in 2018 (regression coefficient 0.012 (95% CI: 0.010-0.013; p < 0.001)). There were no trend changes after introducing NIPT as second-tier (2014) and first-tier test (2017). Conclusions Introducing NIPT did not change the decreasing trend in DS LB prevalence and increasing trend in reduction percentage. These trends may be caused by a broader development of more prenatal testing that had already started before introducing NIPT.

Background Atrioventricular septal defect (AVSD) has an incidence of 4–5.3 per 10.000 live births and is associated with Down syndrome (DS). Data on arrhythmias and sudden cardiac death (SCD) after AVSD correction is scarce. Aim To analyse the incidence of post-operative arrhythmias and SCD after AVSD correction and explore risk factors. Methods This is a retrospective multicenter study including patients after biventricular AVSD correction. Univariate and multivariate analyses were performed to explore risk factors. Results A total of 415 patients were included with a mean follow-up duration of 9 years (range; <30 days–47 years). Early post-operative SVTs were documented in 33 patients (8%) and late post-operative SVTs in 15 patients (3.6%). Non-syndromic AVSD (p = 0.022, HR = 2.64; 95% CI = 1.15–6.04) and cAVSD (p = 0.005, HR = 3.7; 95% CI = 1.39–7.51) were independent risk factors for early post-operative SVTs and significant more late post-operative SVTs occurred in non-syndromic patients (p = 0.016, HR = 6.38; 95% CI = 1.42–28.71) and in pAVSD (p = 0.045, HR = 3.703; 95% CI = 1.03–13.32). Fifteen patients (3.6%) received a pacemaker. Non-syndromic AVSD (p = 0.008, HR = 15.82; 95% CI = 2.04–122.47), pAVSD (p = 0.017, HR = 6.26; 95% CI = 1.39–28.28) and re-operation (p = 0.007, HR = 4.911; 95% CI = 1.54–15.64) were independent risk factors for postoperative pacemaker implantation. Late life-threatening ventricular arrhythmias and SCD occurred in 0.5% and 1.7% respectively. Conclusion There is good long-term survival after AVSD correction and incidence of SCD is low. Non-syndromic AVSD and cAVSD are independent risk factors for early post-operative SVTs. Non-syndromic AVSD patients have significant more early 3rd degree AVB and late post-operative SVTs. Non-syndromic patients with partial AVSD who have undergone reoperation have a significant higher risk of pacemaker implantation.

In the Netherlands, there is no registry system regarding the livebirth prevalence of trisomy 21 (T21). In 2007, a national screening programme was introduced for all pregnant women, which may have changed the livebirth prevalence of T21. The aim of this study is to analyse trends in factors that influence livebirth prevalence of T21 and to estimate the livebirth prevalence of T21 for the period of 2000–2013. National data sets were used on the following: (1) livebirths according to maternal age and (2) prenatal testing and termination of pregnancy (ToP) following diagnosis of T21. These data are combined in a model that uses maternal age-specific risk on T21 and correction factors for natural foetal loss to assess livebirth prevalence of T21. The proportion of mothers aged ≥ 36 years has increased from 12.2% in 2000 to 16.6% in 2009, to gradually decrease afterwards to 15.2% in 2013. The number of invasive tests performed adjusted for total livebirths decreased (5.9% in 2000 vs. 3.2% in 2013) with 0.18% a year (95% CI: −0.21 to −0.15; p < 0.001). Following invasive testing, a higher proportion of foetuses was diagnosed with T21 (1.6% in 2000 vs. 4.8% in 2013) with a significant increase of 0.22% a year (95% CI: 0.18–0.26; p < 0.001). The proportion of ToP subsequent to T21 diagnosis was on average 85.7%, with no clear time trend. This resulted in a stable T21 livebirth prevalence of 13.6 per 10,000 livebirths (regression coefficient −0.025 (95% CI: −0.126 to 0.77; p = 0.60).

Objective To evaluate the (cost-) effectiveness of online consultations in follow-up of patients with celiac disease (CD). Study design Multicenter randomized, controlled trial involving 304 patients aged <= 25 years with CD for >= 1 year, randomized to an online (n = 156) or outpatient consultation (n = 148). An online consultation included questionnaires for symptom and growth measurement. Antitransglutaminase-type-2 antibodies were determined using a point-of-care (POC) test. Controls had a traditional consultation with antitransglutaminase-type-2 antibodies testing in laboratories. Both groups completed questionnaires concerning CD-specific health-related quality of life (HRQOL), gluten-free diet adherence, and patient satisfaction. Six months later, participants repeated HRQOL and patient satisfaction questionnaires and the POC test. The primary outcome was anti-transglutaminase-type-2 antibodies after 6 months, and the secondary outcomes were health problems, dietary adherence, HRQOL, patient satisfaction, and costs. Results The performance of the POC test was inferior to laboratory testing (2/156 positive POC tests vs 13/148 positive laboratory tests; P=.003). Health problems were detected significantly more frequently using online consultation. The detection of growth problems and dietary transgressions was similar. HRQOL (from 1 [good] to 5 [poor]) improved after online consultation (from 3.25 to 3.16 [P=.013] vs controls from 3.10 to 3.23; P=.810). Patient satisfaction (from 1 [low] to 10 [high]) was 7.6 (online) vs 8.0 (controls; P=.001); 58% wished to continue online consultations. Mean costs per participant during the studied period were (sic)202 less for the online group (P<.001). Conclusions The primary outcome could not be tested because the POC test was unreliable. Nevertheless, our results indicate that online consultations for children and young adults with CD are cost saving, increase CDspecific HRQOL, and are satisfactory for the majority.

Abstract Background: Recent studies linking radiation exposure from pediatric computed tomography (CT) to increased risks of leukemia and brain tumors lacked data to control for cancer susceptibility syndromes (CSS). These syndromes might be confounders because they are associated with an increased cancer risk and may increase the likelihood of CT scans performed in children. Methods: We identify CSS predisposing to leukemia and brain tumors through a systematic literature search and summarize prevalence and risk estimates. Because there is virtually no empirical evidence in published literature on patterns of CT use for most types of CSS, we estimate confounding bias of relative risks (RR) for categories of radiation exposure based on expert opinion about the current and previous patterns of CT scans among CSS patients. Results: We estimate that radiation-related RRs for leukemia are not meaningfully confounded by Down syndrome, Noonan syndrome, or other CSS. In contrast, RRs for brain tumors may be overestimated due to confounding by tuberous sclerosis complex (TSC) while von Hippel–Lindau disease, neurofibromatosis type 1, or other CSS do not meaningfully confound. Empirical data on the use of CT scans among CSS patients are urgently needed. Conclusions: Our assessment indicates that associations with leukemia reported in previous studies are unlikely to be substantially confounded by unmeasured CSS, whereas brain tumor risks might have been overestimated due to confounding by TSC. Impact: Future studies should identify TSC patients in order to avoid overestimation of brain tumor risks due to radiation exposure from CT scans. Cancer Epidemiol Biomarkers Prev; 25(1); 114–26. ©2015 AACR.

Objective: Children with Down syndrome (DS) show a delay in cognitive and motor development and have various concomitant health problems. We compared Health-Related Quality of Life (HRQoL) in preschool children with DS with a reference group, and investigated child-related factors (i.e., developmental quotient, adaptive function, health problems, problem behaviour), and maternal level of education on HRQoL. Method: In a cohort of 55 children with DS, HRQoL was measured with the TNO-AZL preschool children Quality of Life Questionnaire (TAPQoL). Data from a reference group were used for comparison. Developmental Quotient (DQ) was assessed with the Bayley Scales of Infant Development II, adaptive function with the Pediatric Evaluation of Disability Inventory, health problems were derived from the medical file, and behavioural problems were measured with the Child Behaviour Checklist. Results: Children with DS (N=55; mean age 41.7 months) scored significantly lower on the TAPQoL domains lung and stomach problems, motor function and communication compared to the reference group. DQ had a significant negative correlation with the domains lung problems and liveliness. Children with DS with respiratory or gastro-intestinal problems showed significant lower scores on lung problems and communication. Problem behavior had a significant negative correlation with the domains sleeping, appetite and social function. A low level of maternal education correlated negatively with positive mood. Adaptive function and congenital heart defect (CHD) did not significantly correlate with HRQoL. Conclusion: Preschool children with DS show a lower HRQoL on particular domains of functioning compared to a normative sample. HRQoL of children with DS is correlated to DQ, respiratory and gastro-intestinal health problems, problem behaviour and maternal education, but not to CHD and adaptive function.

ObjectivesTo analyse which dysmorphic features are most recognised in newborns with Down syndrome (DS). Furthermore to evaluate the communication techniques used by clinicians to inform parents about the postnatal diagnosis and compare these to current best practice guidelines.Study designProspective study of a birth cohort of newborns with DS born between 1 January 2003 and 31 December 2006 registered by the Dutch Paediatric Surveillance Unit (DPSU).ResultsA total of 586 children with trisomy 21 were analysed. Most recognised dysmorphic features in DS newborns were upslanted palpebral fissures' (74.1%; n=426), hypotonia' (73.7%; n=424) and epicanthic folds' (68.5%; n=394). The majority of parents were informed about the suspected diagnosis on the day of birth (76.5%; n=390). Hospital deliveries had a significantly earlier suspected diagnosis (mean age 3-4 days) compared with home deliveries (mean age 7 days) (P<0.05). In 10% (n=44), paediatricians described dissatisfaction with the first conversation with parents. In 88.9% (n=499) parents were both present when the diagnosis was told, however the child was not present during the conversation in 51.3% (n=288). In 10.8% (n=61) parents were not informed about local parent support groups or community resources.ConclusionDS is still often diagnosed after birth, usually on the first day of postnatal life. Most identified clinical features were upslanted palpebral fissures, epicanthic folds and hypotonia. Special attention for recognition of all present clinical features is needed for early diagnosis. Appropriate communication with the parents of the message that their child has DS can be difficult. Guidelines can help to make counselling easier and more effective, which in turn may increase parental satisfaction. Not all recommendations for the first conversation with parents were fully implemented in Dutch clinical practice.

Weijerman ME. De zorg voor kinderen met het downsyndroom. Huisarts Wet 2013;56(10):534-9.

The prevalence of Down syndrome (DS) in the Netherlands is 14/10,000 live births; this is almost 1.5 times higher than during the 1980s and 90 s. In the Netherlands the uptake of prenatal screening is lower than in the rest of Europe and the percentage of pregnant women > 36 years has increased. The early diagnosis and treatment of congenital heart abnormalities means that mortality among DS children has fallen. Although their life expectancy has increased greatly, other comorbidities have come to the fore. Wheezing is reported in 1/3 of the children with DS; it seems unrelated to asthma and atopy. The percentage of mothers who start breastfeeding a child with Down syndrome is low (48%), despite the preventive effect on celiac disease and infections and its therapeutic value for speech and language development. Children with DS score lower on quality of life for the domains of lung and stomach problems, motor function and communication. Medical support and screening addressing specific comorbidities (heart, thyroid, lungs, hearing, vision) and special support for cognitive, motor and speech development in children with Down syndrome is worthwhile.

Children with Down syndrome (DS) have an increased susceptibility to infections, due to altered humoral and/or cellular immunity. The aim of the study was to determine the cytokine production in whole blood of children with DS upon stimulation with heat-killed Streptococcus pneumoniae and lipopolysaccharide (LPS), in comparison with their healthy siblings.Whole blood of 61 children with DS and 57 of their healthy siblings was stimulated with 200 ng/ml LPS and 4 × 10(7) colony-forming units/ml S. pneumoniae during 6, 24, and 48 h. Concentrations of pro- and anti-inflammatory cytokines, tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, IL-8, IL-12p70, and IL-10 were determined at all time points.Children with DS show an increased IL-10 production upon stimulation with S. pneumoniae compared to their healthy siblings. At most time points, no significant differences were seen in cytokine production upon stimulation with LPS.Children with DS may be prone to a severe course of pneumococcal pneumonia, because of an increased anti-inflammatory response.

Children with down syndrome (DS) have an increased susceptibility to infections, due to altered humoral and/or cellular immunity. The aim of this study was to determine the cytokine production in whole blood of children with DS upon stimulation with live influenza A virus.