{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T03:54:50Z","timestamp":1781495690121,"version":"3.54.1"},"reference-count":126,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2026,6,14]],"date-time":"2026-06-14T00:00:00Z","timestamp":1781395200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Down syndrome (DS), caused by trisomy 21, is associated with a wide spectrum of endocrine and gastrointestinal disorders that often arise early in life and significantly impact long-term health. This narrative review examines the pathophysiological mechanisms underlying these conditions, with a particular focus on their bidirectional interactions. Endocrine abnormalities in DS, including thyroid dysfunction, type 1 diabetes mellitus, growth impairment, and altered bone metabolism, occur at higher rates than in the general population and are largely driven by immune dysregulation, chronic inflammation, and gene dosage effects. Similarly, gastrointestinal disorders\u2014ranging from congenital malformations to autoimmune conditions such as celiac disease\u2014are highly prevalent and often present with atypical clinical features. Emerging evidence highlights the central role of gut dysbiosis, characterized by reduced microbial diversity and increased pro-inflammatory taxa, in modulating immune and metabolic pathways. This altered gut environment contributes to a chronic inflammatory state and may promote autoimmunity and endocrine dysfunction through the gut\u2013endocrine\u2013immune axis. Nutritional deficiencies and epigenetic factors, including microRNA dysregulation, further influence disease expression. Understanding this complex cross-talk is essential for improving clinical management. Integrated, multidisciplinary approaches and early screening strategies are crucial to optimize outcomes and guide future research in DS.<\/jats:p>","DOI":"10.3390\/nu18121928","type":"journal-article","created":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T03:01:27Z","timestamp":1781492487000},"page":"1928","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Endocrine and Digestive Disorders Arising in Childhood in Down Syndrome and Their Cross-Talk"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0308-2825","authenticated-orcid":false,"given":"Giuseppe","family":"Cannalire","sequence":"first","affiliation":[{"name":"Pediatrics and Neonatology Unit, University of Parma, Guglielmo da Saliceto Hospital, 29121 Piacenza, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberta","family":"Rotondo","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Parma, 43121 Parma, Italy"},{"name":"Department of Translational Medical Science, Section of Pediatrics, University Federico II, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Donini","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Parma, 43121 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Fradusco","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Parma, 43121 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marialaura","family":"Menzella","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Parma, 43121 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna Giuseppina","family":"Montani","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Parma, 43121 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simone","family":"Pilloni","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Parma, 43121 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-8753-9423","authenticated-orcid":false,"given":"Tommaso","family":"Toschetti","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Parma, 43121 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4103-2837","authenticated-orcid":false,"given":"Susanna","family":"Esposito","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Parma, 43121 Parma, Italy"},{"name":"Pediatric Clinic, University Hospital of Parma, 43121 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7441-9248","authenticated-orcid":false,"given":"Giacomo","family":"Biasucci","sequence":"additional","affiliation":[{"name":"Pediatrics and Neonatology Unit, University of Parma, Guglielmo da Saliceto Hospital, 29121 Piacenza, Italy"},{"name":"Department of Medicine and Surgery, University of Parma, 43121 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8427-8971","authenticated-orcid":false,"given":"Maria Elisabeth","family":"Street","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Parma, 43121 Parma, Italy"},{"name":"Pediatric Clinic, University Hospital of Parma, 43121 Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1281","DOI":"10.1016\/S0140-6736(03)12987-X","article-title":"Down\u2019s syndrome","volume":"361","author":"Roizen","year":"2003","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1038\/s41572-019-0143-7","article-title":"Down syndrome","volume":"6","author":"Antonarakis","year":"2020","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1038\/nrg.2016.154","article-title":"Down syndrome and the complexity of genome dosage imbalance","volume":"18","author":"Antonarakis","year":"2017","journal-title":"Nat. Rev. Genet."},{"key":"ref_4","first-page":"1","article-title":"Genetic and epigenetic pathways in Down syndrome: Insights to the brain and immune system from humans and mouse models","volume":"251","author":"Yu","year":"2020","journal-title":"Prog. Brain Res."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Szeliga, K., Antosz, A., Skrzynska, K., Kalina-Faska, B., Januszek-Trzciakowska, A., and Gawlik, A. (2022). Subclinical hypothyroidism as the most common thyroid dysfunction status in children with Down\u2019s syndrome. Front. Endocrinol., 12.","DOI":"10.3389\/fendo.2021.782865"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"15","DOI":"10.6065\/apem.2142236.118","article-title":"Endocrinal dysfunction in children with Down syndrome","volume":"27","author":"Metwalley","year":"2022","journal-title":"Ann. Pediatr. Endocrinol. Metab."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1016\/j.jpeds.2012.12.087","article-title":"Down syndrome is associated with elevated risk of celiac disease: A nationwide case-control study","volume":"163","author":"Stephansson","year":"2013","journal-title":"J. Pediatr."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"5387","DOI":"10.18632\/oncotarget.23624","article-title":"Prevalence of celiac disease in patients with Down syndrome: A meta-analysis","volume":"9","author":"Du","year":"2018","journal-title":"Oncotarget"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1086","DOI":"10.1177\/0009922820941247","article-title":"Incidence of celiac disease in Down syndrome: A longitudinal, population-based birth cohort study","volume":"59","author":"Ostermaier","year":"2020","journal-title":"Clin. Pediatr."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"264","DOI":"10.12998\/wjcc.v5.i7.264","article-title":"Screening of celiac disease in Down syndrome\u2014Old and new dilemmas","volume":"5","author":"Pavlovic","year":"2017","journal-title":"World J. Clin. Cases"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1041","DOI":"10.1515\/jpem-2016-0073","article-title":"In children with autoimmune thyroid diseases the association with Down syndrome can modify the clustering of extra-thyroidal autoimmune disorders","volume":"29","author":"Aversa","year":"2016","journal-title":"J. Pediatr. Endocrinol. Metab."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2074","DOI":"10.1016\/j.immuni.2022.09.007","article-title":"Excessive negative regulation of type I interferon disrupts viral control in individuals with Down syndrome","volume":"55","author":"Malle","year":"2022","journal-title":"Immunity"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Li, Y., Costiniti, V., Souza Bomfim, G.H., Neginskaya, M., Son, G.Y., Rothermel, B., Pavlov, E., and Lacruz, R.S. (2022). Overexpression of RCAN1, a gene on human chromosome 21, alters cell redox and mitochondrial function in enamel cells. Cells, 11.","DOI":"10.3390\/cells11223576"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"11064","DOI":"10.1007\/s12035-025-04935-0","article-title":"Structural dynamics and network pharmacology for the discovery of inhibitors targeting DYRK1A in neurological disorders","volume":"62","author":"Alam","year":"2025","journal-title":"Mol. Neurobiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1016\/j.nbd.2005.03.020","article-title":"Constitutive Dyrk1A is abnormally expressed in Alzheimer disease, Down syndrome, Pick disease, and related transgenic models","volume":"20","author":"Ferrer","year":"2005","journal-title":"Neurobiol. Dis."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.freeradbiomed.2025.05.432","article-title":"Oxidative stress characterizes the dysfunction of thermogenic adipose tissue in a mouse model of Down syndrome","volume":"237","author":"Castelli","year":"2025","journal-title":"Free Radic. Biol. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1346","DOI":"10.1016\/j.jaci.2014.07.015","article-title":"Defective B-cell memory in patients with Down syndrome","volume":"134","author":"Verstegen","year":"2014","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Huggard, D., Doherty, D.G., and Molloy, E.J. (2020). Immune dysregulation in children with Down syndrome. Front. Pediatr., 8.","DOI":"10.3389\/fped.2020.00073"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1007\/s12016-024-08996-2","article-title":"Down syndrome and autoimmune disease","volume":"66","author":"Hom","year":"2024","journal-title":"Clin. Rev. Allergy Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1038\/s41586-023-05736-y","article-title":"Autoimmunity in Down\u2019s syndrome via cytokines, CD4 T cells and CD11c+ B cells","volume":"615","author":"Malle","year":"2023","journal-title":"Nature"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Cai, S., Lin, J., Li, Z., Liu, S., Feng, Z., Zhang, Y., Zhang, Y., Huang, J., and Chen, Q. (2023). Alterations in intestinal microbiota and metabolites in individuals with Down syndrome and their correlation with inflammation and behavior disorders in mice. Front. Microbiol., 14.","DOI":"10.3389\/fmicb.2023.1016872"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1016\/S1081-1206(10)60516-9","article-title":"Follow-up study of immune defects in patients with dysmorphic disorders","volume":"102","author":"Cruz","year":"2009","journal-title":"Ann. Allergy Asthma Immunol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1111\/j.1365-2265.1994.tb02561.x","article-title":"Susceptibility to autoimmune thyroiditis in Down\u2019s syndrome is associated with the major histocompatibility class II DQA 0301 allele","volume":"41","author":"Nicholson","year":"1994","journal-title":"Clin. Endocrinol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1002\/1096-8628(20010101)98:1<70::AID-AJMG1002>3.0.CO;2-G","article-title":"Prevalence and clinical characteristics of celiac disease in Down syndrome in a US study","volume":"98","author":"Book","year":"2001","journal-title":"Am. J. Med. Genet."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"24231","DOI":"10.1073\/pnas.1908129116","article-title":"Trisomy 21 dysregulates T cell lineages toward an autoimmunity-prone state associated with interferon hyperactivity","volume":"116","author":"Araya","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1477","DOI":"10.1111\/dom.16155","article-title":"Beta cell function and global glucose metabolism are impaired in Dp(16)1Yey mouse model of Down syndrome","volume":"27","author":"Tolu","year":"2025","journal-title":"Diabetes Obes. Metab."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1007\/s10571-017-0514-0","article-title":"Chromosome 21-encoded microRNAs (miRNAs): Impact on Down\u2019s syndrome and trisomy-21 linked disease","volume":"38","author":"Alexandrov","year":"2018","journal-title":"Cell. Mol. Neurobiol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1086\/519248","article-title":"Natural gene-expression variation in Down syndrome modulates the outcome of gene-dosage imbalance","volume":"81","author":"Prandini","year":"2007","journal-title":"Am. J. Hum. Genet."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1007\/s40261-024-01348-0","article-title":"Safety and efficacy of biologic medications and Janus kinase inhibitors in patients with Down syndrome: A retrospective cohort study","volume":"44","author":"Westerkam","year":"2024","journal-title":"Clin. Drug Investig."},{"key":"ref_30","first-page":"11","article-title":"Down syndrome and microRNAs","volume":"8","author":"Rodrigues","year":"2018","journal-title":"Biomed. Rep."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Farroni, C., Marasco, E., Marcellini, V., Giorda, E., Valentini, D., Petrini, S., D\u2019Oria, V., Pezzullo, M., Cascioli, S., and Scarsella, M. (2018). Dysregulated miR-155 and miR-125b are related to impaired B-cell responses in Down syndrome. Front. Immunol., 9.","DOI":"10.3389\/fimmu.2018.02683"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2624","DOI":"10.4161\/cc.20809","article-title":"MiR-1246: A new link of the p53 family with cancer and Down syndrome","volume":"11","author":"Liao","year":"2012","journal-title":"Cell Cycle"},{"key":"ref_33","first-page":"2063","article-title":"Identification of a thymus microRNA-mRNA regulatory network in Down syndrome","volume":"20","author":"Chai","year":"2019","journal-title":"Mol. Med. Rep."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1186\/s12929-016-0265-0","article-title":"Integrated miRNA and mRNA expression profiling in fetal hippocampus with Down syndrome","volume":"23","author":"Shi","year":"2016","journal-title":"J. Biomed. Sci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"7497","DOI":"10.18632\/oncotarget.7120","article-title":"Modular transcriptional repertoire and microRNA target analyses characterize genomic dysregulation in the thymus of Down syndrome infants","volume":"7","author":"Bando","year":"2016","journal-title":"Oncotarget"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1159\/000504669","article-title":"The role of microRNAs in influencing body growth and development","volume":"93","author":"Cirillo","year":"2020","journal-title":"Horm. Res. Paediatr."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.cytogfr.2017.12.004","article-title":"MicroRNAs link chronic inflammation in childhood to growth impairment and insulin resistance","volume":"39","author":"Cirillo","year":"2018","journal-title":"Cytokine Growth Factor Rev."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1146\/annurev-immunol-042718-041841","article-title":"Gut microbiota regulation of T cells during inflammation and autoimmunity","volume":"37","author":"Brown","year":"2019","journal-title":"Annu. Rev. Immunol."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Aversa, T., Corica, D., Zirilli, G., Pajno, G.B., Salzano, G., De Luca, F., and Wasniewska, M. (2019). Phenotypic expression of autoimmunity in children with autoimmune thyroid disorders. Front. Endocrinol., 10.","DOI":"10.3389\/fendo.2019.00476"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1159\/000457952","article-title":"Characterization of thyroid abnormalities in a large cohort of children with Down syndrome","volume":"87","author":"Pierce","year":"2017","journal-title":"Horm. Res. Paediatr."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1507\/endocrj.EJ25-0345","article-title":"Age-related changes in thyroid hormone profile in pediatric patients with Down syndrome","volume":"73","author":"Toki","year":"2026","journal-title":"Endocr. J."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Szybiak-Skora, W., Cyna, W., and Lacka, K. (2025). Autoimmune thyroid disease in patients with Down syndrome\u2014Review. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26010029"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"113","DOI":"10.4103\/0971-5916.164218","article-title":"Oxidative stress, thyroid dysfunction and Down syndrome","volume":"142","author":"Campos","year":"2015","journal-title":"Indian J. Med. Res."},{"key":"ref_44","first-page":"e240032","article-title":"Graves\u2019 disease in children with Down syndrome","volume":"13","author":"Cebeci","year":"2024","journal-title":"Endocr. Connect."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1530\/EJE-09-0751","article-title":"Peculiarities of Graves\u2019 disease in children and adolescents with Down\u2019s syndrome","volume":"162","author":"Corrias","year":"2010","journal-title":"Eur. J. Endocrinol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1111\/j.1365-2265.2008.03419.x","article-title":"Hyperthyroidism in a population with Down syndrome","volume":"71","author":"Corretger","year":"2009","journal-title":"Clin. Endocrinol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1096","DOI":"10.1111\/apa.15153","article-title":"Multiorgan involvement and management in children with Down syndrome","volume":"109","author":"Lagan","year":"2020","journal-title":"Acta Paediatr."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1136\/adc.87.2.97","article-title":"Growth charts for Down\u2019s syndrome from birth to 18 years of age","volume":"87","author":"Myrelid","year":"2002","journal-title":"Arch. Dis. Child."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"111317","DOI":"10.1016\/j.brainresbull.2025.111317","article-title":"Association of neurodegeneration, cognitive impairment, and short stature in Down syndrome; Could proinflammatory cytokines be the common factor?","volume":"224","author":"Sadeghi","year":"2025","journal-title":"Brain Res. Bull."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Shaki, D., Hershkovitz, E., Tamam, S., Bollotin, A., David, O., Yalovitsky, G., Loewenthal, N., Carmon, L., Walker, D., and Nowak, R. (2023). GH treatment in pediatric Down syndrome: A systematic review and mini meta-analysis. Front. Endocrinol., 14.","DOI":"10.3389\/fendo.2023.1135768"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"3070","DOI":"10.1002\/ajmg.a.37366","article-title":"Down syndrome birth weight in England and Wales: Implications for clinical practice","volume":"167A","author":"Morris","year":"2015","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1007\/s12098-013-1249-7","article-title":"Diagnosis and management of Down syndrome","volume":"81","author":"Kabra","year":"2014","journal-title":"Indian J. Pediatr."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1087","DOI":"10.1038\/ejcn.2013.137","article-title":"Resting energy expenditure and adiposity accretion among children with Down syndrome: A 3-year prospective study","volume":"67","author":"Hill","year":"2013","journal-title":"Eur. J. Clin. Nutr."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1161\/CIRCULATIONAHA.122.059706","article-title":"Cardiovascular complications of Down syndrome: Scoping review and expert consensus","volume":"147","author":"Dimopoulos","year":"2023","journal-title":"Circulation"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"2892","DOI":"10.2337\/dc22-0482","article-title":"Diabetes and obesity in Down syndrome across the lifespan: A retrospective cohort study using U.K. electronic health records","volume":"45","author":"Aslam","year":"2022","journal-title":"Diabetes Care"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1038\/nm.3820","article-title":"A high-throughput chemical screen reveals that harmine-mediated inhibition of DYRK1A increases human pancreatic beta cell replication","volume":"21","author":"Wang","year":"2015","journal-title":"Nat. Med."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1070","DOI":"10.1007\/s00125-010-1686-z","article-title":"Down\u2019s syndrome in diabetic patients aged <20 years: An analysis of metabolic status, glycaemic control and autoimmunity in comparison with type 1 diabetes","volume":"53","author":"Rohrer","year":"2010","journal-title":"Diabetologia"},{"key":"ref_58","first-page":"562","article-title":"Characteristics of type 1 diabetes mellitus in children and adolescents with Down\u2019s syndrome in an admixed population","volume":"65","author":"Pessoa","year":"2021","journal-title":"Arch. Endocrinol. Metab."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1038\/nrendo.2009.80","article-title":"Endocrine and musculoskeletal abnormalities in patients with Down syndrome","volume":"5","author":"Hawli","year":"2009","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Moreau, M., Benhaddou, S., Dard, R., Tolu, S., Hamz\u00e9, R., Vialard, F., Movassat, J., and Janel, N. (2021). Metabolic diseases and Down syndrome: How are they linked together?. Biomedicines, 9.","DOI":"10.3390\/biomedicines9020221"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"116471","DOI":"10.1016\/j.bone.2022.116471","article-title":"Low bone mass and impaired fracture healing in mouse models of trisomy 21 (Down syndrome)","volume":"162","author":"Sherman","year":"2022","journal-title":"Bone"},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Erdo\u011fan, F., and G\u00fcven, A. (2022). Is there a secular trend regarding puberty in children with Down syndrome?. Front. Endocrinol., 13.","DOI":"10.3389\/fendo.2022.1001985"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"2151","DOI":"10.1007\/s00198-010-1443-7","article-title":"Bone mass in male and female children and adolescents with Down syndrome","volume":"22","author":"Moreno","year":"2011","journal-title":"Osteoporos. Int."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"2847","DOI":"10.1007\/s00198-013-2393-7","article-title":"Bone mass and density in preadolescent boys with and without Down syndrome","volume":"24","author":"Wu","year":"2013","journal-title":"Osteoporos. Int."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"4304","DOI":"10.1016\/j.ridd.2013.08.037","article-title":"Effects of calcium and training on the development of bone density in children with Down syndrome","volume":"34","author":"Reza","year":"2013","journal-title":"Res. Dev. Disabil."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"896758","DOI":"10.1155\/2015\/896758","article-title":"Determinants of vitamin D levels in children and adolescents with Down syndrome","volume":"2015","author":"Stagi","year":"2015","journal-title":"Int. J. Endocrinol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"5687","DOI":"10.1093\/hmg\/ddv284","article-title":"Rescue of the abnormal skeletal phenotype in Ts65Dn Down syndrome mice using genetic and therapeutic modulation of trisomic Dyrk1a","volume":"24","author":"Blazek","year":"2015","journal-title":"Hum. Mol. Genet."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1007\/s11657-023-01348-1","article-title":"The aetiology of atypical bone health in individuals with Down syndrome","volume":"18","author":"Duong","year":"2023","journal-title":"Arch. Osteoporos."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1016\/j.crvi.2006.06.004","article-title":"The growth capacity of bone marrow CD34-positive cells in culture is drastically reduced in a murine model of Down syndrome","volume":"329","author":"Jablonska","year":"2006","journal-title":"Comptes Rendus Biol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1426","DOI":"10.1002\/ajmg.a.61258","article-title":"Gastrointestinal disorders in Down syndrome","volume":"179","author":"Bermudez","year":"2019","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1007\/s00383-008-2188-7","article-title":"Down syndrome and the enteric nervous system","volume":"24","author":"Moore","year":"2008","journal-title":"Pediatr. Surg. Int."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"586","DOI":"10.1007\/s00383-004-1236-1","article-title":"Does Down syndrome affect the outcome of congenital duodenal obstruction?","volume":"20","author":"Singh","year":"2004","journal-title":"Pediatr. Surg. Int."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1111\/j.1399-0004.2008.01110.x","article-title":"Congenital gastrointestinal defects in Down syndrome: A report from the Atlanta and National Down Syndrome Projects","volume":"75","author":"Freeman","year":"2009","journal-title":"Clin. Genet."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"748","DOI":"10.1111\/j.1440-1746.2005.03996.x","article-title":"Long-term continence in patients with Hirschsprung\u2019s disease and Down syndrome","volume":"21","author":"Trajanovska","year":"2006","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1146\/annurev-immunol-040210-092915","article-title":"Integration of genetic and immunological insights into a model of celiac disease pathogenesis","volume":"29","author":"Abadie","year":"2011","journal-title":"Annu. Rev. Immunol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1542\/peds.56.1.131","article-title":"A case of Down\u2019s syndrome complicated by retinoblastoma and celiac disease","volume":"56","author":"Bentley","year":"1975","journal-title":"Pediatrics"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"e2022057010","DOI":"10.1542\/peds.2022-057010","article-title":"Health supervision for children and adolescents with Down syndrome","volume":"149","author":"Bull","year":"2022","journal-title":"Pediatrics"},{"key":"ref_78","first-page":"589","article-title":"Celiac disease in children with Down syndrome","volume":"90","year":"2019","journal-title":"Rev. Chil. Pediatr."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"387","DOI":"10.5001\/omj.2018.72","article-title":"Occurrence of hypothyroidism, diabetes mellitus, and celiac disease in Emirati children with Down\u2019s syndrome","volume":"33","author":"Abdulrazzaq","year":"2018","journal-title":"Oman Med. J."},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Kyritsi, E.M., and Kanaka-Gantenbein, C. (2020). Autoimmune thyroid disease in specific genetic syndromes in childhood and adolescence. Front. Endocrinol., 11.","DOI":"10.3389\/fendo.2020.00543"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"e20","DOI":"10.1097\/MPG.0000000000000858","article-title":"An unusual manifestation of celiac disease in an adolescent with Down syndrome and Graves disease","volume":"65","author":"Creo","year":"2017","journal-title":"J. Pediatr. Gastroenterol. Nutr."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1016\/j.jpeds.2008.08.007","article-title":"Prospective human leukocyte antigen, endomysium immunoglobulin A antibodies, and transglutaminase antibodies testing for celiac disease in children with Down syndrome","volume":"154","author":"Wouters","year":"2009","journal-title":"J. Pediatr."},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Gatti, S., Gelzoni, G., Catassi, G.N., and Catassi, C. (2021). The clinical spectrum of inflammatory bowel disease associated with specific genetic syndromes: Two novel pediatric cases and a systematic review. Front. Pediatr., 9.","DOI":"10.3389\/fped.2021.742830"},{"key":"ref_84","first-page":"220","article-title":"Down\u2019s syndrome and inflammatory bowel disease: Is there a real link?","volume":"106","year":"2014","journal-title":"Rev. Esp. Enferm. Dig."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"e70330","DOI":"10.1002\/alz.70330","article-title":"Gut dysbiosis in Down syndrome: A potentially unexplored culprit for early Alzheimer\u2019s disease","volume":"21","author":"Rosas","year":"2025","journal-title":"Alzheimers Dement."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"5187","DOI":"10.2147\/JIR.S280953","article-title":"Interferon-driven immune dysregulation in Down syndrome: A review of the evidence","volume":"14","author":"Chung","year":"2021","journal-title":"J. Inflamm. Res."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.arcped.2019.11.008","article-title":"Feeding problems and gastrointestinal diseases in Down syndrome","volume":"27","author":"Ravel","year":"2020","journal-title":"Arch. P\u00e9diatr."},{"key":"ref_88","unstructured":"Nguyen, K.-D., Duong, S., Lazare, F., Triantafyllopoulou, M., Leibowitz, I., Butzner, J.D., Nagpal, R., and Treem, W.R. (2009). Autoimmune hepatitis in Down syndrome. Down Syndr. Res. Pract., Available online: https:\/\/www.down-syndrome.org\/en-us\/library\/research-practice\/online\/2009\/autoimmune-hepatitis-down-syndrome\/."},{"key":"ref_89","doi-asserted-by":"crossref","unstructured":"Borrego-Ruiz, A., and Borrego, J.J. (2024). Neurodevelopmental disorders associated with gut microbiome dysbiosis in children. Children, 11.","DOI":"10.3390\/children11070796"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"154938","DOI":"10.1016\/j.cyto.2019.154938","article-title":"Increased systemic inflammation in children with Down syndrome","volume":"127","author":"Huggard","year":"2020","journal-title":"Cytokine"},{"key":"ref_91","first-page":"e45510","article-title":"Biofilm\u2019s impact on inflammatory bowel diseases","volume":"15","author":"Palandurkar","year":"2023","journal-title":"Cureus"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"2301","DOI":"10.2169\/internalmedicine.53.1980","article-title":"Immune-mediated protein-losing enteropathy with Down syndrome","volume":"53","author":"Nanjo","year":"2014","journal-title":"Intern. Med."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1111\/jir.13042","article-title":"Micronutrient status in children and adolescents with Down syndrome: Systematic review and meta-analysis","volume":"67","year":"2023","journal-title":"J. Intellect. Disabil. Res."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1007\/s00787-021-01799-2","article-title":"Altered gut microbiota correlates with cognitive impairment in Chinese children with Down\u2019s syndrome","volume":"31","author":"Ren","year":"2022","journal-title":"Eur. Child Adolesc. Psychiatry"},{"key":"ref_95","doi-asserted-by":"crossref","unstructured":"Ferrari, M., and Stagi, S. (2021). Autoimmunity and genetic syndromes: A focus on Down syndrome. Genes, 12.","DOI":"10.3390\/genes12020268"},{"key":"ref_96","first-page":"98","article-title":"Autoimmunity puzzle in Down syndrome","volume":"12","author":"Badiu","year":"2010","journal-title":"Down Syndr. Res. Pract."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1007\/s11894-025-01001-6","article-title":"Fecal microbiota transplantation for disorders of gut-brain interaction: Current insights, effectiveness, and future perspectives","volume":"27","author":"Arif","year":"2025","journal-title":"Curr. Gastroenterol. Rep."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1186\/s11689-023-09503-y","article-title":"Hypovitaminosis D in persons with Down syndrome and autism spectrum disorder","volume":"15","author":"Boyd","year":"2023","journal-title":"J. Neurodev. Disord."},{"key":"ref_99","doi-asserted-by":"crossref","unstructured":"Saghazadeh, A., Mahmoudi, M., Dehghani Ashkezari, A., Oliaie Rezaie, N., and Rezaei, N. (2017). Systematic review and meta-analysis shows a specific micronutrient profile in people with Down syndrome: Lower blood calcium, selenium and zinc, higher red blood cell copper and zinc, and higher salivary calcium and sodium. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0175437"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"936","DOI":"10.1038\/jp.2014.116","article-title":"Revisiting early hypothyroidism screening in infants with Down syndrome","volume":"34","author":"Purdy","year":"2014","journal-title":"J. Perinatol."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"101666","DOI":"10.1016\/j.molmet.2022.101666","article-title":"Dysregulated systemic metabolism in a Down syndrome mouse model","volume":"68","author":"Sarver","year":"2023","journal-title":"Mol. Metab."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.neubiorev.2016.11.022","article-title":"Therapeutic role of sirtuins in neurodegenerative disease and their modulation by polyphenols","volume":"73","author":"Ajami","year":"2017","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1016\/S1474-4422(16)30034-5","article-title":"Safety and efficacy of cognitive training plus epigallocatechin-3-gallate in young adults with Down\u2019s syndrome (TESDAD): A double-blind, randomized, placebo-controlled, phase 2 trial","volume":"15","author":"Pujol","year":"2016","journal-title":"Lancet Neurol."},{"key":"ref_104","doi-asserted-by":"crossref","unstructured":"Andreu-Fern\u00e1ndez, V., Almeida Toledano, L., Pizarro, N., Navarro-Tapia, E., G\u00f3mez-Roig, M.D., de la Torre, R., and Garc\u00eda-Algar, \u00d3. (2020). Bioavailability of epigallocatechin gallate administered with different nutritional strategies in healthy volunteers. Antioxidants, 9.","DOI":"10.3390\/antiox9050440"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"1032","DOI":"10.1016\/j.clnu.2015.05.009","article-title":"Reply: Green tea EGCG plus fish oil omega-3 dietary supplements rescue mitochondrial dysfunctions and are safe in a Down\u2019s syndrome child","volume":"34","year":"2015","journal-title":"Clin. Nutr."},{"key":"ref_106","doi-asserted-by":"crossref","unstructured":"Fakhri, S., Gravandi, M.M., Abdian, S., Akkol, E.K., Farzaei, M.H., and Sobarzo-S\u00e1nchez, E. (2021). The neuroprotective role of polydatin: Neuropharmacological mechanisms, molecular targets, therapeutic potentials, and clinical perspective. Molecules, 26.","DOI":"10.3390\/molecules26195985"},{"key":"ref_107","doi-asserted-by":"crossref","unstructured":"Karami, A., Fakhri, S., Kooshki, L., and Khan, H. (2022). Polydatin: Pharmacological mechanisms, therapeutic targets, biological activities, and health benefits. Molecules, 27.","DOI":"10.3390\/molecules27196474"},{"key":"ref_108","doi-asserted-by":"crossref","unstructured":"Scala, I., Valenti, D., Scotto D\u2019Aniello, V., Marino, M., Riccio, M.P., Bravaccio, C., Vacca, R.A., and Strisciuglio, P. (2021). Epigallocatechin-3-Gallate Plus Omega-3 Restores the Mitochondrial Complex I and F0F1-ATP Synthase Activities in PBMCs of Young Children with Down Syndrome: A Pilot Study of Safety and Efficacy. Antioxidants, 10.","DOI":"10.3390\/antiox10030469"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"110170","DOI":"10.1016\/j.neuropharm.2024.110170","article-title":"Reversal of neurodevelopmental impairment and cognitive enhancement by pharmacological intervention with the polyphenol polydatin in a Down syndrome model","volume":"261","author":"Emili","year":"2024","journal-title":"Neuropharmacology"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1016\/j.freeradbiomed.2025.04.032","article-title":"Polydatin reactivates mitochondrial bioenergetics and mitophagy while preventing premature senescence by modulating microRNA-155 and its direct targets in human fibroblasts with trisomy 21","volume":"235","author":"Valenti","year":"2025","journal-title":"Free Radic. Biol. Med."},{"key":"ref_111","doi-asserted-by":"crossref","unstructured":"Hisbiyah, Y., Endaryanto, A., Setyoboedi, B., Rochmah, N., Faizi, M., and Fedora, K. (2023). Selenium level correlates negatively with antibodies but positively with thyroid function in children with Down syndrome: An Indonesian study. Front. Endocrinol., 14.","DOI":"10.3389\/fendo.2023.1177373"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"1395","DOI":"10.53730\/ijhs.v6nS9.12765","article-title":"Effectiveness of selenium supplementation in children with autoimmune thyroiditis","volume":"6","author":"Hisbiyah","year":"2022","journal-title":"Int. J. Health Sci."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1016\/j.mehy.2007.01.068","article-title":"Down syndrome and thyroid dysfunction: Should nutritional support be the first-line treatment?","volume":"69","author":"Thiel","year":"2007","journal-title":"Med. Hypotheses"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"259","DOI":"10.3109\/00207459209003299","article-title":"Zinc affects the metabolism of thyroid hormones in children with Down\u2019s syndrome: Normalization of thyroid stimulating hormone and of reversal triiodothyronine plasmic levels by dietary zinc supplementation","volume":"65","author":"Licastro","year":"1992","journal-title":"Int. J. Neurosci."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1007\/BF02784425","article-title":"Zinc sulfate supplementation improves thyroid function in hypozincemic Down children","volume":"67","author":"Bucci","year":"1999","journal-title":"Biol. Trace Elem. Res."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1007\/s12011-008-8280-y","article-title":"Effect of zinc supplementation on thyroid hormone metabolism of adolescents with Down syndrome","volume":"129","author":"Marreiro","year":"2009","journal-title":"Biol. Trace Elem. Res."},{"key":"ref_117","doi-asserted-by":"crossref","unstructured":"\u017bur, S., Sokal, A., Sta\u015bkiewicz-Bartecka, W., Kiciak, A., Grajek, M., Krupa-Kotara, K., Kowalski, O., and Bia\u0142ek-Dratwa, A. (2025). Nutrition for children with Down syndrome\u2014Current knowledge, challenges, and clinical recommendations: A narrative review. Healthcare, 13.","DOI":"10.3390\/healthcare13172222"},{"key":"ref_118","doi-asserted-by":"crossref","unstructured":"Wang, Y., Zhang, L., Wang, X., Yuan, X., Huang, Q., Wang, H., Song, Q., Li, D., Kan, H., and Li, J. (2025). Investigating the associations between dietary nutrient intake and risk of Hashimoto\u2019s thyroiditis: A cross-sectional study from NHANES and a case-control study. Front. Nutr., 12.","DOI":"10.3389\/fnut.2025.1731662"},{"key":"ref_119","unstructured":"Gaisford, S. (2021). New Study on Probiotics and Constipation in DS, Down\u2019s Syndrome Research Foundation. Available online: https:\/\/www.dsrf-uk.org\/probioticsconstipation\/."},{"key":"ref_120","first-page":"2206","article-title":"Safety and preliminary efficacy on cognitive performance and adaptive functionality of epigallocatechin gallate (EGCG) in children with Down syndrome: A randomized phase Ib clinical trial (PERSEUS study)","volume":"24","author":"Langohr","year":"2022","journal-title":"Genet. Med."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1016\/j.clnu.2015.04.012","article-title":"Green tea EGCG plus fish oil omega-3 dietary supplements rescue mitochondrial dysfunctions and are safe in a Down\u2019s syndrome child","volume":"34","author":"Vacca","year":"2015","journal-title":"Clin. Nutr."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"e9","DOI":"10.1017\/S0954422423000082","article-title":"Protective effects of polydatin against bone and joint disorders: The in vitro and in vivo evidence so far","volume":"37","author":"Zhang","year":"2024","journal-title":"Nutr. Res. Rev."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1038\/s41419-018-0635-5","article-title":"A new inhibitor of glucose-6-phosphate dehydrogenase blocks pentose phosphate pathway and suppresses malignant proliferation and metastasis in vivo","volume":"9","author":"Mele","year":"2018","journal-title":"Cell Death Dis."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1002\/biof.184","article-title":"Mitochondrial dysfunction and Down\u2019s syndrome: Is there a role for coenzyme Q10?","volume":"37","author":"Tiano","year":"2011","journal-title":"Biofactors"},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1016\/j.pediatrneurol.2007.08.003","article-title":"Coenzyme Q10 (ubiquinol-10) supplementation improves oxidative imbalance in children with trisomy 21","volume":"37","author":"Miles","year":"2007","journal-title":"Pediatr. Neurol."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.pediatrneurol.2005.11.004","article-title":"Coenzyme Q10 absorption and tolerance in children with Down syndrome: A dose-ranging trial","volume":"35","author":"Miles","year":"2006","journal-title":"Pediatr. Neurol."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/18\/12\/1928\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T03:37:35Z","timestamp":1781494655000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/18\/12\/1928"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,14]]},"references-count":126,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["nu18121928"],"URL":"https:\/\/doi.org\/10.3390\/nu18121928","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,14]]}}}