Clinical practice - latest insights in optimizing the care of children with Down syndrome.

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.

Neonatal mortality and morbidity in Down syndrome in the time of prenatal aneuploidy testing: a retrospective cohort study.

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.

Decreased Antibody Response After Severe Acute Respiratory Syndrome Coronavirus 2 Vaccination in Patients With Down Syndrome.

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. CLINICAL TRIALS REGISTRATION: NCT05145348.

Does non-invasive prenatal testing affect the livebirth prevalence of Down syndrome in the Netherlands? A population-based register study.

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.

Older mothers and increased impact of prenatal screening: stable livebirth prevalence of trisomy 21 in the Netherlands for the period 2000-2013.

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).

E-Healthcare for Celiac Disease-A Multicenter Randomized Controlled Trial.

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 €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 CD-specific HRQOL, and are satisfactory for the majority. TRIAL REGISTRATION: Trialregister.nl: NTR3688.

Incidence and risk factors of post-operative arrhythmias and sudden cardiac death after atrioventricular septal defect (AVSD) correction: Up to 47years of follow-up.

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 9years (range; <30days-47years). 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.

Confounding of the association between radiation exposure from CT scans and risk of leukemia and brain tumors by cancer susceptibility syndromes.

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 pediatric CT scans. We identify CSS predisposing to leukemia and brain tumors through a systematic literature search and summarize prevalence and risk. Since empirical evidence is lacking 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 patterns of CT scans among CSS patients. We estimate that radiation-related RRs for leukemia are not meaningfully confounded by Down syndrome, Noonan syndrome and other CSS. Moreover, tuberous sclerosis complex, von Hippel-Lindau disease, neurofibromatosis type 1 and other CSS do not meaningfully confound RRs for brain tumors. Empirical data on the use of CT scans among CSS patients is urgently needed. Our assessment indicates that associations with radiation exposure from pediatric CT scans and leukemia or brain tumors reported in previous studies are unlikely to be substantially confounded by unmeasured CSS.

Confounding of the Association between Radiation Exposure from CT Scans and Risk of Leukemia and Brain Tumors by Cancer Susceptibility Syndromes.

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.

Respiratory syncytial virus prophylaxis in Down syndrome: a prospective cohort study.

BACKGROUND AND OBJECTIVES: Children with Down syndrome (DS) are at significant risk for respiratory syncytial virus (RSV) infection and related hospitalization. We compared hospitalization rates due to respiratory tract infection in children with DS aged <2 years who prospectively received palivizumab during the RSV season with a previously published, similar untreated DS birth cohort. METHODS: A total of 532 children with DS who prospectively received palivizumab were assembled from the prospective Canadian RSV Evaluation Study of Palivizumab registry between 2005 and 2012. The untreated group included 233 children with DS derived from a nationwide Dutch birth cohort from 2003 to 2005. Events during the RSV seasons were counted. Poisson regression analysis was performed to compare incidence rate ratios (95% confidence intervals [CIs]) between groups while controlling for observation length and known risk factors for severe RSV infection. RESULTS: In total, 31 (23 untreated, 8 treated) RSV-related hospitalizations were documented. The adjusted risk of RSV-related hospitalizations was higher in untreated subjects than in palivizumab recipients (incidence rate ratio 3.63; 95% CI, 1.52-8.67). The adjusted risk of hospitalization for all respiratory tract infection (147 events; 73 untreated, 74 treated) was similar (incidence rate ratio untreated versus palivizumab 1.11; 95% CI, 0.80-1.55). CONCLUSIONS: These results suggest that palivizumab is associated with a 3.6-fold reduction in the incidence rate ratio for RSV-related hospitalization in children with DS during the first 2 years of life. A randomized trial is needed to determine the efficacy of RSV immunoprophylaxis in this specific high-risk patient population.

Increased production of interleukin-10 in children with Down syndrome upon ex vivo stimulation with Streptococcus pneumoniae.

BACKGROUND: 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. METHODS: 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)-1ß, IL-6, IL-8, IL-12p70, and IL-10 were determined at all time points. RESULTS: 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. CONCLUSION: Children with DS may be prone to a severe course of pneumococcal pneumonia, because of an increased anti-inflammatory response.

[New insights into the support of children with Down syndrome]. / Nieuwe inzichten voor de begeleiding van kinderen met het syndroom van Down.

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.

Frequency of lower respiratory tract infections in relation to adaptive immunity in children with Down syndrome compared to their healthy siblings.

AIM: Children with Down syndrome (DS) experience respiratory tract infections (RTIs) more frequently than healthy children. We investigated whether this is related to different immunological characteristics associated with DS. METHODS: The study group consisted of 22 children with DS and 22 of their healthy, age-range matched siblings. Data were collected on infections and hospitalizations because of lower RTIs. Immunoglobulin and IgG subclass levels in blood, as well as lymphocyte and T cell (subset) counts, were determined. RESULTS: The children with DS had a significantly higher frequency of lower RTIs and related hospitalization than their siblings. We also found significantly reduced IgG2 levels as well as significantly lower counts of total lymphocytes, CD4(+) T lymphocytes, CD4(+) invariant natural killer (iNKT) cells and regulatory T cells in the DS group. CONCLUSION: In children with DS, reduced levels of IgG2, total lymphocytes, T lymphocytes, iNKT cells and regulatory T cells might contribute to their higher susceptibility to lower RTIs.

Testicular volume and testicular microlithiasis in boys with Down syndrome.

PURPOSE: Studies have suggested that testicular microlithiasis and Down syndrome are linked, yet a correlation remains unclear. We investigated the prevalence of testicular microlithiasis in patients with Down syndrome. We hypothesized that testicular microlithiasis is present at a higher rate in these patients. We further hypothesized that patients with Down syndrome have lower testicular volumes than normal age matched boys. We tested our hypothesis by ultrasound investigation in boys 0 to 18 years old with Down syndrome. MATERIALS AND METHODS: Testicular ultrasound was performed in 79 boys with Down syndrome. Mean patient age was 8.8 years (range 0.4 to 18.3). Testicular microlithiasis was assessed and testicular volume was measured according to the formula, π/6 × length × width × height. RESULTS: Testicular microlithiasis was present in 18 boys (22.8%). It was diagnosed in 6 of 28 boys younger than 7 years (21.4%), in 6 of 28 boys 7 to 12 years (21.4%) and in 6 of 23 boys 12 years or older (26.1%). No significant difference was found in the prevalence of testicular microlithiasis between these 3 groups. Mean testicular volumes in patients with Down syndrome (2.19 ml) were significantly smaller than the normative values. CONCLUSIONS: This study demonstrated a 22.8% prevalence of testicular microlithiasis in boys with Down syndrome, which is significantly increased compared to normative values. In addition, testis volume is significantly smaller in boys with Down syndrome compared to normative values.

Increased pro-inflammatory cytokine production in Down Syndrome children upon stimulation with live influenza A virus.

PURPOSE: 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. METHODS: Whole blood of 61 children with DS and 57 of their healthy siblings was stimulated with 2.5 × 10(4) TCID50/ml influenza A virus during 6, 24, and 48 h. TNF-α, IL-1ß, IL-6, IL-8, IL-10, IL-12p70, IFN-α, IFN-γ concentrations, and viral load were measured at all time points. RESULTS: At most of the time points, TNF-α, IL-1ß, IL-6, and IL-8 concentrations were significantly higher in children with DS following stimulation with live influenza A virus. IFN-α and IFN-γ levels were also significantly higher in the DS group. Viral clearance, however, was equal in both groups. CONCLUSIONS: Children with DS have an altered immune response to influenza A virus. The production of higher levels of pro-inflammatory cytokines may be responsible for a more severe clinical course of viral disease in these children.

Recurrent wheeze in children with Down syndrome: is it asthma?

AIM: To compare the prevalence of current wheeze in children with Down syndrome (DS), their siblings, and nonrelated population controls. METHODS: This was a case-control study in which the International Study of Asthma and Allergy in Childhood questionnaire for respiratory symptoms was completed by parents for 130 children with DS, 167 of their siblings, and for 119 age- and sex-matched control subjects from the general population. RESULTS: Both wheeze ever and wheeze during the last 12 months was more commonly reported in DS than in their siblings or controls. The relative risk (RR) of current wheeze in DS was 2.8 (95% CI, 1.42-5.51) compared with siblings, and 2.75 (95% CI, 1.28-5.88) compared with controls. A doctor's diagnosis of asthma was found in 3.1% in children with DS, in 4.2% in siblings and in 6.7% in controls. During 4-years follow-up, the diagnosis of asthma could not be confirmed in the 24 DS children with current wheeze, and atopy was found in none of them. CONCLUSION: Wheeze is common in children with DS. This is likely to be related to the factors specific for DS and probably unrelated to asthma.

Increased risk of respiratory tract infections in children with Down syndrome: the consequence of an altered immune system.

Down syndrome (DS) is the most common chromosomal abnormality among live-born infants. Respiratory tract infections are the most important cause of mortality in individuals with DS at all ages. In recent decades several studies have been performed to elucidate abnormalities of the immune system in DS. However, the influence of the immune system on the occurrence of respiratory tract infections in these children has never been reviewed.

Clinical practice. The care of children with Down syndrome.

Down syndrome (DS) is one of the most common chromosomal abnormalities. Because of medical advances and improvements in overall medical care, the median survival of individuals with DS has increased considerably. This longer life expectancy requires giving the necessary care to the individual with DS over their total longer lifespan. DS medical guidelines are designed for the optimal care of the child in whom a diagnosis of DS has been confirmed. We present an overview of the most important issues related to children with DS based on the most relevant literature currently available.

Prevalence of congenital heart defects and persistent pulmonary hypertension of the neonate with Down syndrome.

The aim of this study was to assess the prevalence of congenital heart defects (CHDs) and persistent pulmonary hypertension of the neonate (PPHN) in children with Down syndrome (DS) and to assess its impact on neonatal factors. It was a prospective study of a birth cohort of children with DS born between 2003 and 2006 registered by the Dutch Paediatric Surveillance Unit (DPSU). A CHD occurred in 43% of 482 children with trisomy 21. Atrioventricular septal defect was found in 54%, ventricular septal defect in 33.3% and patent ductus arteriosus in 5.8%. The incidence of PPHN in DS was 5.2%, which is significantly higher than the general population (p < 0.001). The reported mortality in newborns with DS was overall 3.3% and was still significant higher in children with a CHD versus no CHD (5.8% versus 1.5%) (p = 0.008). The presence of CHD in children with DS had no influence on their birth weight, mean gestational age and Apgar score. In neonates with DS, we found not only a 43% prevalence of CHD, but also a high incidence of PPHN at 5.2%. Early recognition of the cardiac condition of neonates with DS seems justified.

Intestinal barrier gene variants may not explain the increased levels of antigliadin antibodies, suggesting other mechanisms than altered permeability.

Various genes may influence intestinal barrier function, including MAGI2, MYO9B, and PARD3, which are associated with celiac disease. Because direct measurement of intestinal permeability is difficult, antibodies against gliadin (AGA) and Baker's yeast (anti-Saccharomyces cerevisiae antibodies [ASCA]) can be used as an indirect test. The objective of this study was to investigate whether intestinal permeability, represented by AGA, was correlated with MAGI2, MYO9B, and PARD3. Analyses were performed in patients with Down syndrome, a population with suspected increased intestinal permeability. Correlations between AGA and ASCA were investigated. Patients with Down syndrome (n = 126) were genotyped for six single-nucleotide polymorphisms in MAGI2 (rs1496770, rs6962966, rs9640699), MYO9B (rs1457092, rs2305764), and PARD3 (rs10763976). An allele dosage association of these risk genes and AGA levels was performed. The correlation between AGA and ASCA was studied. A strong correlation was found between AGA and ASCA (p < 0.01). The patient group with one or more risk genotypes had lower mean AGA levels (trend test p = 0.007) and consisted of a larger number of patients with normal AGA levels (p = 9.3 x 10(-5)). Celiac-associated risk genotypes are associated with lower AGA values instead of elevated ones. Thus, other immunologic phenomena play a role in the increased prevalence of elevated AGA in patients with Down syndrome, possibly involving altered induction and/or maintenance of tolerance.