{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,17]],"date-time":"2026-01-17T23:42:43Z","timestamp":1768693363415,"version":"3.49.0"},"reference-count":43,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2023,9,15]],"date-time":"2023-09-15T00:00:00Z","timestamp":1694736000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Angelman Syndrome (AS) is a rare genetic disorder caused by lack of maternal UBE3A protein due to a deletion of the chromosome 15q11.2-q13 region, uniparental paternal disomy, imprinting center defect, or pathogenic variant in the UBE3A gene. Characteristics are developmental delay, epilepsy, behavioral, and sleep problems. There is some evidence for hyperphagia, shorter stature, and higher BMI compared to neurotypical children, but longitudinal studies on growth are lacking. In this study, we analyzed prospectively collected data of 145 children with AS, who visited the ENCORE Expertise Center between 2010 and 2021, with a total of 853 visits. Children showed an elevated mean score of 25 on the Dykens Hyperphagia questionnaire (range 11\u201355) without genotype association. Higher scores were significantly associated with higher body mass index (BMI) standard deviation scores (SDS) (p = 0.004). Mean height was \u22121.2 SDS (SD 1.3), mean BMI-SDS was 0.6 (SD 1.7); 43% had a BMI-SDS &gt; 1 and 20% had a BMI-SDS &gt; 2. Higher BMI-SDS was significantly associated with non-deletion genotype (p = 0.037) and walking independently (p = 0.023). Height SDS decreased significantly with age (p &lt; 0.001) and BMI-SDS increased significantly with age (p &lt; 0.001. Onset of puberty was normal. In conclusion, children with AS showed moderate hyperphagia, lower height SDS, and higher BMI-SDS compared to norm data, with increasing deviation from the norm with age. It is uncertain how loss of maternal UBE3A function may influence growth. Attention to diet, exercise, and hyperphagia from an early age is recommended to prevent obesity and associated health problems.<\/jats:p>","DOI":"10.3390\/jcm12185981","type":"journal-article","created":{"date-parts":[[2023,9,15]],"date-time":"2023-09-15T04:06:13Z","timestamp":1694750773000},"page":"5981","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Hyperphagia, Growth, and Puberty in Children with Angelman Syndrome"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7887-5558","authenticated-orcid":false,"given":"Karen G. C. B.","family":"Bindels-de Heus","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Erasmus MC Sophia Children\u2019s Hospital, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands"},{"name":"ENCORE Expertise Center for Neurodevelopmental Disorders, Erasmus MC, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-9274-6316","authenticated-orcid":false,"given":"Doesjka A","family":"Hagenaar","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Erasmus MC Sophia Children\u2019s Hospital, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands"},{"name":"ENCORE Expertise Center for Neurodevelopmental Disorders, Erasmus MC, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands"},{"name":"Department of Child- and Adolescent Psychiatry and Psychology, Erasmus MC Sophia Children\u2019s Hospital, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ilonka","family":"Dekker","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Erasmus MC Sophia Children\u2019s Hospital, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6408-1717","authenticated-orcid":false,"given":"Danielle C. M.","family":"van der Kaay","sequence":"additional","affiliation":[{"name":"Department of Pediatric Endocrinology, Erasmus MC Sophia Children\u2019s Hospital, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gerthe F.","family":"Kerkhof","sequence":"additional","affiliation":[{"name":"Department of Pediatric Endocrinology, Erasmus MC Sophia Children\u2019s Hospital, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"name":"ENCORE Expertise Center for AS","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3758-1297","authenticated-orcid":false,"given":"Ype","family":"Elgersma","sequence":"additional","affiliation":[{"name":"ENCORE Expertise Center for Neurodevelopmental Disorders, Erasmus MC, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands"},{"name":"Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marie-Claire Y.","family":"de Wit","sequence":"additional","affiliation":[{"name":"ENCORE Expertise Center for Neurodevelopmental Disorders, Erasmus MC, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands"},{"name":"Department of Neurology and Pediatric Neurology, Erasmus MC Sophia Children\u2019s Hospital, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9088-8095","authenticated-orcid":false,"given":"Sabine E.","family":"Mous","sequence":"additional","affiliation":[{"name":"ENCORE Expertise Center for Neurodevelopmental Disorders, Erasmus MC, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands"},{"name":"Department of Child- and Adolescent Psychiatry and Psychology, Erasmus MC Sophia Children\u2019s Hospital, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Henriette A.","family":"Moll","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Erasmus MC Sophia Children\u2019s Hospital, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands"},{"name":"ENCORE Expertise Center for Neurodevelopmental Disorders, Erasmus MC, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,9,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1002\/ajmg.a.31074","article-title":"Angelman syndrome 2005: Updated consensus for diagnostic criteria","volume":"140","author":"Williams","year":"2006","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1002\/ajmg.a.61382","article-title":"An overview of health issues and development in a large clinical cohort of children with Angelman syndrome","volume":"182","author":"Mous","year":"2020","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2197","DOI":"10.1002\/ajmg.a.36058","article-title":"Angelman syndrome in Denmark. birth incidence, genetic findings, and age at diagnosis","volume":"161A","author":"Mertz","year":"2013","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1038\/ng0197-70","article-title":"UBE3A\/E6-AP mutations cause Angelman syndrome","volume":"15","author":"Kishino","year":"1997","journal-title":"Nat. Genet."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1326","DOI":"10.1038\/s41431-019-0435-0","article-title":"Update of the EMQN\/ACGS best practice guidelines for molecular analysis of Prader-Willi and Angelman syndromes","volume":"27","author":"Beygo","year":"2019","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1136\/jmg.38.12.834","article-title":"Distinct phenotypes distinguish the molecular classes of Angelman syndrome","volume":"38","author":"Lossie","year":"2001","journal-title":"J. Med. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1002\/ajmg.a.33775","article-title":"Angelman syndrome: Mutations influence features in early childhood","volume":"155A","author":"Tan","year":"2011","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1002\/ajmg.a.36831","article-title":"Increased body mass in infancy and early toddlerhood in Angelman syndrome patients with uniparental disomy and imprinting center defects","volume":"167A","author":"Brennan","year":"2015","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2681","DOI":"10.1016\/j.ridd.2014.07.025","article-title":"Eating behavior, prenatal and postnatal growth in Angelman syndrome","volume":"35","author":"Mertz","year":"2014","journal-title":"Res. Dev. Disabil."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1002\/ajmg.a.36923","article-title":"Are Angelman and Prader-Willi syndromes more similar than we thought? Food-related behavior problems in Angelman, Cornelia de Lange, fragile X, Prader-Willi and 1p36 deletion syndromes","volume":"167A","author":"Welham","year":"2015","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"106161","DOI":"10.1016\/j.appet.2022.106161","article-title":"Measuring hyperphagia in patients with monogenic and syndromic obesity","volume":"178","author":"Zorn","year":"2022","journal-title":"Appetite"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1816","DOI":"10.1038\/oby.2007.216","article-title":"Assessment of hyperphagia in Prader-Willi syndrome","volume":"15","author":"Dykens","year":"2007","journal-title":"Obesity"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1038\/s41572-023-00435-4","article-title":"Child and adolescent obesity","volume":"9","author":"Lister","year":"2023","journal-title":"Nat. Rev. Dis. Prim."},{"key":"ref_14","unstructured":"(2021, April 05). TNO Groeidiagrammen. Available online: https:\/\/www.tno.nl\/nl\/gezond\/werk-jeugd-gezondheid\/jeugd\/eerste-1000-dagen-kind\/groeidiagrammen-groeicalculators\/."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Schundeln, M.M., Marschke, L., Bauer, J.J., Hauffa, P.K., Schweiger, B., Fuhrer-Sakel, D., Lahner, H., Poeppel, T.D., Kiewert, C., and Hauffa, B.P. (2016). A Piece of the Puzzle: The Bone Health Index of the BoneXpert Software Reflects Cortical Bone Mineral Density in Pediatric and Adolescent Patients. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0151936"},{"key":"ref_16","unstructured":"IBM (IBM SPSS Statistics for Windows, 2017). IBM SPSS Statistics for Windows, Version 25.0."},{"key":"ref_17","unstructured":"R. Core Team (2021). R: A Language and Environment for Statistical Computing, R. Foundation for Statistical Computing. Available online: https:\/\/www.R-project.org\/."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1","DOI":"10.18637\/jss.v067.i01","article-title":"Fitting Linear Mixed-Effects Models Using lme4","volume":"67","author":"Bates","year":"2015","journal-title":"J. Stat. Softw."},{"key":"ref_19","first-page":"41","article-title":"Prader-Willi and Angelman Syndromes: Mechanisms and Management","volume":"16","author":"Ma","year":"2023","journal-title":"Appl. Clin. Genet."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1159\/000489824","article-title":"Appetite-Related Eating Behaviours: An Overview of Assessment Methods, Determinants and Effects on Children\u2019s Weight","volume":"73","author":"Freitas","year":"2018","journal-title":"Ann. Nutr. Metab."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"4563","DOI":"10.1007\/s00018-021-03800-2","article-title":"The circadian clock and metabolic homeostasis: Entangled networks","volume":"78","author":"Oster","year":"2021","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1016\/j.neuron.2017.06.014","article-title":"Toward a Wiring Diagram Understanding of Appetite Control","volume":"95","author":"Andermann","year":"2017","journal-title":"Neuron"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1038\/nrendo.2014.91","article-title":"Hormonal and neural mechanisms of food reward, eating behaviour and obesity","volume":"10","author":"Murray","year":"2014","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1016\/j.cub.2014.12.047","article-title":"Ube3a imprinting impairs circadian robustness in Angelman syndrome models","volume":"25","author":"Shi","year":"2015","journal-title":"Curr. Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1016\/j.molmet.2019.09.012","article-title":"Circadian clock network desynchrony promotes weight gain and alters glucose homeostasis in mice","volume":"30","author":"Kolbe","year":"2019","journal-title":"Mol. Metab."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"104444","DOI":"10.1016\/j.ridd.2023.104444","article-title":"Sleep problems in children with Angelman Syndrome: The effect of a behavioral intervention program","volume":"135","author":"Legerstee","year":"2023","journal-title":"Res. Dev. Disabil."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Viho, E.M.G., Punt, M., Distel, B., Houtman, R., Kroon, J., Elgersma, Y., and Meijer, O.C. (2022). The Hippocampal Response to Acute Corticosterone Elevation Is Altered in a Mouse Model for Angelman Syndrome. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24010303"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1111\/jir.12702","article-title":"Profiles of atypical sensory processing in Angelman, Cornelia de Lange and Fragile X syndromes","volume":"64","author":"Heald","year":"2020","journal-title":"J. Intellect. Disabil. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1040","DOI":"10.1002\/ajmg.a.33951","article-title":"Nutritional Phases in Prader-Willi Syndrome","volume":"155a","author":"Miller","year":"2011","journal-title":"Am. J. Med. Genet. Part A"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Fan, H.C., Wang, S.Y., Peng, Y.J., and Lee, H.S. (2020). Valproic Acid Impacts the Growth of Growth Plate Chondrocytes. Int. J. Environ. Res. Public Health, 17.","DOI":"10.3390\/ijerph17103675"},{"key":"ref_31","unstructured":"CBS (2023, July 26). Centraal Bureau Voor Statistiek. Available online: https:\/\/www.cbs.nl\/nl-nl\/cijfers\/detail\/81565NED?q=gewicht%20kinderen."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1002\/ajmg.a.61940","article-title":"Clinical aspects of a large group of adults with Angelman syndrome","volume":"185","author":"Jong","year":"2021","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"476","DOI":"10.3389\/fnmol.2018.00476","article-title":"UBE3A: An E3 Ubiquitin Ligase with Genome-Wide Impact in Neurodevelopmental Disease","volume":"11","author":"Lopez","year":"2018","journal-title":"Front. Mol. Neurosci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1038\/nn1845","article-title":"Rescue of neurological deficits in a mouse model for Angelman syndrome by reduction of alphaCaMKII inhibitory phosphorylation","volume":"10","author":"Harris","year":"2007","journal-title":"Nat. Neurosci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"905","DOI":"10.3945\/an.117.016253","article-title":"Energy Metabolism Profile in Individuals with Prader-Willi Syndrome and Implications for Clinical Management: A Systematic Review","volume":"8","author":"Alsaif","year":"2017","journal-title":"Adv. Nutr."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1159\/000504300","article-title":"Nutrition Assessment and Intervention in a Pediatric Patient with Angelman Syndrome: A Case Presentation Highlighting Clinical Challenges and Evidence-Based Solutions","volume":"13","author":"Fisher","year":"2020","journal-title":"Lifestyle Genom."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"e1843","DOI":"10.1002\/mgg3.1843","article-title":"A multidisciplinary approach and consensus statement to establish standards of care for Angelman syndrome","volume":"10","author":"Duis","year":"2022","journal-title":"Mol. Genet. Genomic Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1327","DOI":"10.1002\/ajmg.a.38694","article-title":"Angelman syndrome in adolescence and adulthood: A retrospective chart review of 53 cases","volume":"176","author":"Prasad","year":"2018","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1111\/ppe.12507","article-title":"Timing of puberty in boys and girls: A population-based study","volume":"33","author":"Brix","year":"2019","journal-title":"Paediatr. Perinat. Epidemiol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"101265","DOI":"10.1016\/j.beem.2019.03.001","article-title":"Puberty: Normal physiology (brief overview)","volume":"33","author":"Wood","year":"2019","journal-title":"Best. Pract. Res. Clin. Endocrinol. Metab."},{"key":"ref_41","unstructured":"(2023, July 26). Lengtegroei. Available online: https:\/\/www.jgzrichtlijnen.nl\/alle-richtlijnen\/richtlijn\/?richtlijn=48&rlpag=2775."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1376","DOI":"10.1210\/jc.2014-3631","article-title":"Evaluation of 451 Danish boys with delayed puberty: Diagnostic use of a new puberty nomogram and effects of oral testosterone therapy","volume":"100","author":"Lawaetz","year":"2015","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_43","unstructured":"Hannema, S.E. (2023, July 26). Werkboek Kinderendocrinologie\/Late Puberteit Jongens. Available online: https:\/\/nvk.medonline.nl\/kinderendocrinologie\/late-of-geen-verschijnselen-van-puberteit-jongen\/."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/12\/18\/5981\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:51:32Z","timestamp":1760129492000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/12\/18\/5981"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,9,15]]},"references-count":43,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2023,9]]}},"alternative-id":["jcm12185981"],"URL":"https:\/\/doi.org\/10.3390\/jcm12185981","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,9,15]]}}}