{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T13:31:12Z","timestamp":1768570272236,"version":"3.49.0"},"posted":{"date-parts":[[2025,6,23]]},"group-title":"Neurology","reference-count":44,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,6,23]],"date-time":"2025-06-23T00:00:00Z","timestamp":1750636800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,6,23]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background and objectives<\/jats:title>\n                  <jats:p>Macrocephaly is among the most common findings in neurofibromatosis type 1 (NF1) and may be associated with other clinical manifestations of the genetic syndrome. NF1-specific growth charts that account for expected macrocephaly may increase sensitivity to detect atypical growth. We aimed to produce NF1-specific growth charts of head circumference for the age range of 0 to 3 years and to assess their potential clinical impact.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Using electronic health records from the Children\u2019s Hospital of Philadelphia, we collected head circumference measurements from children with NF1 and a community control cohort seen at scheduled well-child visits. We compared head circumference normed using Center for Disease Control (CDC) growth charts between these groups over time. We constructed NF1-specific growth charts using two independent methods. Finally, we used mixed-effects models to relate the resulting centile scores with developmental delay assessed with the Survey of Well-being of Young Children.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    Our dataset contained 2180 observations from 305 individuals (167 male) with NF1, and 104,750 observations from 16,742 individuals (8809 male) in the community control cohort, all aged 0 to 3 years old. Head circumference was significantly elevated in NF1 throughout the age range (\n                    <jats:italic>P<\/jats:italic>\n                    <jats:sub>adjusted<\/jats:sub>\n                    &lt;0.05), but the effect sizes varied nonlinearly with age, starting moderate at 1 month (\n                    <jats:italic>d<\/jats:italic>\n                    = 0.56), then small at four months (\n                    <jats:italic>d<\/jats:italic>\n                    = 0.28), moderate again at 15 months (\n                    <jats:italic>d<\/jats:italic>\n                    = 0.58), and finally large at 28 months (\n                    <jats:italic>d<\/jats:italic>\n                    = 0.8). NF1-specific growth curves demonstrated slower rate-of-growth for head circumference in the first two months of life yet more sustained growth over time. Although none of the children with NF1 met the standard for microcephaly according to CDC charts, smaller head circumference benchmarked against NF1-specific charts was correlated with developmental delay (standardized beta = 0.24;\n                    <jats:italic>P<\/jats:italic>\n                    = 0.013).\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Discussion<\/jats:title>\n                  <jats:p>We present the first NF1-specific growth charts for head circumference covering ages 0 to 3 years. Macrocephaly in NF1 becomes more exaggerated over time as rate-of-growth is sustained compared to controls. Smaller head size relative to NF1 growth expectations is not captured by CDC charts yet nevertheless relates to developmental delay, suggesting that NF1-specific charts may increase sensitivity to clinically concerning patterns of growth in children with NF1.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.06.23.25328558","type":"posted-content","created":{"date-parts":[[2025,6,24]],"date-time":"2025-06-24T00:10:12Z","timestamp":1750723812000},"source":"Crossref","is-referenced-by-count":0,"title":["NF1-specific growth charts for head circumference over the first three years of life"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0780-3864","authenticated-orcid":false,"given":"Ayan S.","family":"Mandal","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Russell T.","family":"Shinohara","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Benjamin","family":"Jung","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Margaret","family":"Gardner","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Habib E.","family":"Akouri","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Benjamin E.","family":"Yerys","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Whitney","family":"Guthrie","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kelly M.","family":"Janke","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John D.","family":"Herrington","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew C.","family":"Hocking","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gareth","family":"Ball","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonathan M.","family":"Payne","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kathryn N.","family":"North","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nils","family":"Muhlert","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shruti","family":"Garg","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jakob","family":"Seidlitz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael J.","family":"Fisher","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aaron","family":"Alexander-Bloch","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2025062505100644000_2025.06.23.25328558v1.1","first-page":"71","volume-title":"Arch Dermatol","volume":"2005","year":"2005"},{"key":"2025062505100644000_2025.06.23.25328558v1.2","first-page":"625","volume-title":"Acta Neuropathol","volume":"2020","year":"2020"},{"key":"2025062505100644000_2025.06.23.25328558v1.3","first-page":"1845","volume-title":"Neuro Oncol","volume":"2022","year":"2022"},{"key":"2025062505100644000_2025.06.23.25328558v1.4","first-page":"713","volume-title":"Nature","volume":"1992","year":"1992"},{"key":"2025062505100644000_2025.06.23.25328558v1.5","first-page":"275","volume-title":"Cell","volume":"1992","year":"1992"},{"key":"2025062505100644000_2025.06.23.25328558v1.6","first-page":"4450","volume-title":"Oncogene","volume":"1999","year":"1999"},{"key":"2025062505100644000_2025.06.23.25328558v1.7","first-page":"403","volume-title":"J Transl Genet Genom","volume":"2022","year":"2022"},{"key":"2025062505100644000_2025.06.23.25328558v1.8","first-page":"325","volume-title":"Neurolog\u00eda","volume":"2022","year":"2022"},{"key":"2025062505100644000_2025.06.23.25328558v1.9","first-page":"239","volume-title":"Neuropediatrics","volume":"2002","year":"2002"},{"key":"2025062505100644000_2025.06.23.25328558v1.10","doi-asserted-by":"crossref","unstructured":"Mandal AS , Dorfschmidt L , Schabdach JM , et al. Normative trajectories of extra-axial cerebrospinal fluid during childhood and adolescence defined in a clinically-acquired MRI dataset [online]. medRxiv 2024. p. 2024.09.24.24314251. Accessed at: https:\/\/www.medrxiv.org\/content\/10.1101\/2024.09.24.24314251v1.abstract. Accessed April 18, 2025.","DOI":"10.1101\/2024.09.24.24314251"},{"key":"2025062505100644000_2025.06.23.25328558v1.11","first-page":"810","volume-title":"AJNR Am J Neuroradiol","volume":"2001","year":"2001"},{"key":"2025062505100644000_2025.06.23.25328558v1.12","first-page":"1540","volume-title":"J Child Neurol","volume":"2016","year":"2016"},{"key":"2025062505100644000_2025.06.23.25328558v1.13","first-page":"32","volume-title":"J Neurodev Disord","volume":"2015","year":"2015"},{"key":"2025062505100644000_2025.06.23.25328558v1.14","unstructured":"Kuczmarski RJ , Ogden CL , Grummer-Strawn LM , et al. CDC growth charts: United States. Adv Data. Adv Data; Epub 2000 Jun 8.:1\u201327."},{"key":"2025062505100644000_2025.06.23.25328558v1.15","first-page":"563","volume-title":"Biol Psychiatry","volume":"2013","year":"2013"},{"key":"2025062505100644000_2025.06.23.25328558v1.16","first-page":"137","volume-title":"Trends Neurosci","volume":"2008","year":"2008"},{"key":"2025062505100644000_2025.06.23.25328558v1.17","first-page":"467","volume-title":"Arch Gen Psychiatry","volume":"2011","year":"2011"},{"key":"2025062505100644000_2025.06.23.25328558v1.18","first-page":"317","volume-title":"Neuropsychol Rev","volume":"2018","year":"2018"},{"key":"2025062505100644000_2025.06.23.25328558v1.19","first-page":"645","volume-title":"Dev Med Child Neurol","volume":"2015","year":"2015"},{"key":"2025062505100644000_2025.06.23.25328558v1.20","first-page":"948","volume-title":"Am J Med Genet A","volume":"2023","year":"2023"},{"key":"2025062505100644000_2025.06.23.25328558v1.21","first-page":"317","article-title":"Neurofibromatosis Type 1 Growth Charts","volume":"1999","year":"1999","journal-title":"J Med Genet"},{"key":"2025062505100644000_2025.06.23.25328558v1.22","doi-asserted-by":"crossref","unstructured":"Szudek J , Birch P , Friedman JM . Growth charts for young children with neurofibromatosis 1 (NF1). Am. J. Med. Genet. Wiley; 2000. p. 224\u2013228.","DOI":"10.1002\/(SICI)1096-8628(20000529)92:3<224::AID-AJMG12>3.3.CO;2-A"},{"key":"2025062505100644000_2025.06.23.25328558v1.23","first-page":"e230096","article-title":"Brain Growth Charts for Quantitative Analysis of Pediatric Clinical Brain MRI Scans with Limited Imaging Pathology","volume":"2023","year":"2023","journal-title":"Radiology"},{"key":"2025062505100644000_2025.06.23.25328558v1.24","unstructured":"Flegal KM , Cole TJ . Construction of LMS parameters for the Centers for Disease Control and Prevention 2000 growth charts. Natl Health Stat Report. Natl Health Stat Report; Epub 2013 Feb 11.:1\u20133."},{"key":"2025062505100644000_2025.06.23.25328558v1.25","first-page":"7","volume-title":"Psychol Sci","volume":"2014","year":"2014"},{"key":"2025062505100644000_2025.06.23.25328558v1.26","doi-asserted-by":"crossref","unstructured":"Low KJ , Foreman J , Hobson RJ , et al. The LMSz method - an automatable scalable approach to constructing gene-specific growth charts in rare disorders [online]. Genetic and Genomic Medicine medRxiv; 2024. Accessed at: https:\/\/www.medrxiv.org\/content\/10.1101\/2024.08.19.24312213v1.full.pdf.","DOI":"10.1101\/2024.08.19.24312213"},{"key":"2025062505100644000_2025.06.23.25328558v1.27","doi-asserted-by":"crossref","unstructured":"Rigby R , Stasinopoulos D. Generalized additive models for location, scale and shape. Journal of the Royal Statistical Society: Series C (Applied Statistics) [online serial]. 2005;54. Accessed at: https:\/\/www.gamlss.com\/wp-content\/uploads\/2023\/06\/DistributionsForModellingLocationScaleandShape-1.pdf.","DOI":"10.1111\/j.1467-9876.2005.00510.x"},{"key":"2025062505100644000_2025.06.23.25328558v1.28","first-page":"e836","volume-title":"Pediatrics","volume":"2010","year":"2010"},{"key":"2025062505100644000_2025.06.23.25328558v1.29","unstructured":"WHO child growth standards: head circumference-for-age, arm circumference-for-age, triceps skinfold-for-age and subscapular skinfold-for-age: methods and development [online]. World Health Organization; 2007. Accessed at: https:\/\/www.who.int\/publications\/i\/item\/9789241547185. Accessed April 18, 2025."},{"key":"2025062505100644000_2025.06.23.25328558v1.30","first-page":"577","volume-title":"Acad Pediatr","volume":"2013","year":"2013"},{"key":"2025062505100644000_2025.06.23.25328558v1.31","first-page":"e20190374","volume-title":"Pediatrics","volume":"2019","year":"2019"},{"key":"2025062505100644000_2025.06.23.25328558v1.32","first-page":"200","volume-title":"J Pediatr","volume":"2021","year":"2021"},{"key":"2025062505100644000_2025.06.23.25328558v1.33","first-page":"1173","volume-title":"Am J Med Genet A","volume":"2019","year":"2019"},{"key":"2025062505100644000_2025.06.23.25328558v1.34","first-page":"45","article-title":"Developmental trajectories in infants and pre-school children with Neurofibromatosis 1","volume":"2024","year":"2024","journal-title":"Mol Autism"},{"key":"2025062505100644000_2025.06.23.25328558v1.35","first-page":"51","volume-title":"Autism Res","volume":"2013","year":"2013"},{"key":"2025062505100644000_2025.06.23.25328558v1.36","first-page":"239","volume-title":"Psychiatry Res","volume":"2015","year":"2015"},{"key":"2025062505100644000_2025.06.23.25328558v1.37","first-page":"2277","volume-title":"Am J Med Genet A","volume":"2022","year":"2022"},{"key":"2025062505100644000_2025.06.23.25328558v1.38","first-page":"461","volume-title":"Biol Psychiatry","volume":"2025","year":"2025"},{"key":"2025062505100644000_2025.06.23.25328558v1.39","first-page":"2372","volume-title":"Hum Brain Mapp","volume":"2014","year":"2014"},{"key":"2025062505100644000_2025.06.23.25328558v1.40","first-page":"e1204","article-title":"Growth charts for children with Down syndrome in the United States","volume":"2015","year":"2015","journal-title":"Pediatrics"},{"key":"2025062505100644000_2025.06.23.25328558v1.41","first-page":"243","volume-title":"Am J Med Genet A","volume":"2024","year":"2024"},{"key":"2025062505100644000_2025.06.23.25328558v1.42","first-page":"2477","volume-title":"Stat Med","volume":"1994","year":"1994"},{"key":"2025062505100644000_2025.06.23.25328558v1.43","first-page":"357","volume-title":"Nat Commun","volume":"2019","year":"2019"},{"key":"2025062505100644000_2025.06.23.25328558v1.44","first-page":"525","article-title":"Brain charts for the human lifespan","volume":"2022","year":"2022","journal-title":"Nature"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2025.06.23.25328558","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T20:39:01Z","timestamp":1768509541000},"score":1,"resource":{"primary":{"URL":"http:\/\/medrxiv.org\/lookup\/doi\/10.1101\/2025.06.23.25328558"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,23]]},"references-count":44,"URL":"https:\/\/doi.org\/10.1101\/2025.06.23.25328558","relation":{},"subject":[],"published":{"date-parts":[[2025,6,23]]},"subtype":"preprint"}}