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Cited by 253Autism Spectrum Disorder ResearchGenetics and Neurodevelopmental DisordersChild Nutrition and Feeding Issues

Head circumference and brain size in autism spectrum disorder: A systematic review and meta-analysis

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Sacco, Roberto, Gabriele, Stefano, Persico, Antonio M.·2015·Psychiatry Research: Neuroimaging
DOI 10.1016/j.pscychresns.2015.08.016
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Abstract

Macrocephaly and brain overgrowth have been associated with autism spectrum disorder. We performed a systematic review and meta-analysis to provide an overall estimate of effect size and statistical significance for both head circumference and total brain volume in autism. Our literature search strategy identified 261 and 391 records, respectively; 27 studies defining percentages of macrocephalic patients and 44 structural brain imaging studies providing total brain volumes for patients and controls were included in our meta-analyses. Head circumference was significantly larger in autistic compared to control individuals, with 822/5225 (15.7%) autistic individuals displaying macrocephaly. Structural brain imaging studies measuring brain volume estimated effect size. The effect size is higher in low functioning autistics compared to high functioning and ASD individuals. Brain overgrowth was recorded in 142/1558 (9.1%) autistic patients. Finally, we found a significant interaction between age and total brain volume, resulting in larger head circumference and brain size during early childhood. Our results provide conclusive effect sizes and prevalence rates for macrocephaly and brain overgrowth in autism, confirm the variation of abnormal brain growth with age, and support the inclusion of this endophenotype in multi-biomarker diagnostic panels for clinical use.

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  • A subset of individuals with ASD has increased brain size and head circumference relative to normal age-based values.

    “The brain size as well as the head circumference of a subset of subjects with ASD is increased compared to normal age-based values (see meta-analysis in [308]).”

    From Autism spectrum disorder: neuropathology and animal models (2017) · cites this paper as [308]

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  1. Akshoomoff, N., Lord, C., Lincoln, A.J., Courchesne, R.Y., Carper, R.A., Townsend, J., Courchesne, E., 2004. Outcome classification of preschool children with autism spectrum disorders using MRI brain measures. Journal of American Academy of Child and Adolescent Psychiatry, 43, 349-57.
  2. American Psychiatric Association, 2013. Diagnostic and statistical manual of mental disorders (5th ed.). American Psychiatric Publishing: Arlington, VA.
  3. Bloss, C.S., Courchesne, E., 2007. MRI neuroanatomy in young girls with autism: a preliminary study. Journal of American Academy of Child and Adolescent Psychiatry 46, 515-23.
  4. Bolton, P., Macdonald, H., Pickles, A., Rios, P., Goode, S., Crowson, M., Bailey, A., Rutter, M., 1994. A case-control family history study of autism. Journal of Child Psychology and Psychiatry 35, 877-900.
  5. Buxbaum, J.D., Cai, G., Chaste, P., Nygren, G., Goldsmith, J., Reichert, J., Anckarsäter, H., Rastam, M., Smith, C.J., Silverman, J.M., Hollander E., Leboyer, M., Gillberg, C., Verloes, A., Betancur, C., 2007. Mutation screening of the PTEN gene in patients with autism spectrum disorders and macrocephaly. American Journal of Medical Genetics B Neuropsychiatric Genetics 144B, 484-491.
  6. Cleavinger, H.B., Bigler, E.D., Johnson, J.L., Lu, J., McMahon, W., Lainhart, J.E., 2008. Quantitative magnetic resonance image analysis of the cerebellum in macrocephalicand normocephalic children and adults with autism. Journal of International Neuropsychological Society 14, 401-13.
  7. Constantino, J.N., Majmudar, P., Bottini, A., Arvin, M., Virkud, Y., Simons, P., Spitznagel, E., 2010. Infant head growth in male siblings of children with and without autism spectrum disorders. Journal of Neurodevelopmental Disorders 2, 39-46.
  8. Courchesne, E., Carper, R., Akshoomoff, N., 2003. Evidence of brain overgrowth in the first year of life in autism. The Journal of the American Medical Association 290, 337-44.
  9. Courchesne, E., Press, G.A., Yeung-Courchesne, R., 1993. Parietal lobe abnormalities detected with MR in patients with infantile autism. American Journal of Roentgenology 160, 387-93.
  10. Courchesne, E., Yeung-Courchesne, R., Press, G.A., Hesselink, J.R., Jernigan, T.L., 1988: Hypoplasia of cerebellar vermal lobules VI and VII in autism. New England Journal of Medicine 318, 1349-54.
  11. Davidovitch, M., Golan, D., Vardi, O., Lev, D., Lerman-Sagie, T., 2011. Israeli children with autism spectrum disorder are not macrocephalic. Journal of Child Neurology 26, 580-5.
  12. Davidovitch, M., Patterson, B., Gartside, P., 1996. Head circumference measurements in children with autism. Journal of Child Neurology 11, 389-93.
  13. Deutsch, C.K., Joseph, R.M., 2003. Brief report: cognitive correlates of enlarged head circumference in children with autism. Journal of Autism and Developmental Disorders 33, 209- 215.
  14. Ecker, C., Marquand, A., Mourão-Miranda, J., Johnston, P., Daly, E.M., Brammer, M.J., Maltezos, S., Murphy, C.M., Robertson, D., Williams, S.C., Murphy, D.G., 2010. Describing the brain in autism in five dimensions--magnetic resonance imaging-assisted diagnosis of autism spectrum disorder using a multiparameter classification approach. Journal of Neuroscience 30, 10612-23.
  15. Fombonne, E., Rogé, B., Claverie, J., Courty, S., Frémolle, J., 1999. Microcephaly and macrocephaly in autism. Journal of Autism and Developmental Disorders 29, 113-9.
  16. Froehlich, W., Cleveland, S., Torres, A., Phillips, J., Cohen, B., Torigoe, T., Miller, J., Fedele, A., Collins, J., Smith, K., Lotspeich, L., Croen, L.A., Ozonoff, S., Lajonchere, C., Grether, J.K., Hallmayer, J., 2013. Head Circumferences in Twins With and Without Autism Spectrum Disorders. Journal of Autism and Developmental Disorders 43, 2026-37.
  17. Ghaziuddin, M., Zaccagnini, J., Tsai, L., Elardo, S., 1999. Is megalencephaly specific to autism? Journal of Intellectual Disability Research 43, 279-82.
  18. Gottesman, I.I., Shields, J., 1973. Genetic theorizing and schizophrenia. British Journal of Psychiatry 122, 15-30.
  19. Griebling, J., Minshew, N.J., Bodner, K., Libove, R., Bansal, R., Konasale, P., Keshavan, M.S., Hardan, A., 2010. Dorsolateral prefrontal cortex magnetic resonance imaging measurements and cognitive performance in autism. Journal of Child Neurology 25, 856-63.
  20. Hardan, A.Y., Girgis, R.R., Adams, J., Gilbert, A.R., Melhem, N.M., Keshavan, M.S., Minshew, N.J., 2008. Brief report: abnormal association between the thalamus and brain size in Asperger's disorder. Journal of Autism and Developmental Disorders 38, 390-4.
  21. Hardan, A.Y., Minshew, N.J., Harenski, K., Keshavan, M.S., 2000. Posterior fossa magnetic resonance imaging in autism. Journal of American Academy of Child and Adolescent Psychiatry 40, 666-72.
  22. Jou, R.J., Minshew, N.J., Keshavan, M.S., Hardan, A.Y., 2010a. Cortical gyrification in autistic and Asperger disorders: a preliminary magnetic resonance imaging study. Journal of Child Neurology 25, 1462-7.
  23. Kates, W.R., Burnette, C.P., Eliez, S., Strunge, L.A., Kaplan, D., Landa, R., Reiss, A.L., Pearlson, G.D., 2004. Neuroanatomic variation in monozygotic twin pairs discordant for the narrow phenotype for autism. American Journal of Psychiatry 161, 539-46.
  24. Lainhart, J.E., Bigler, E.D., Bocian, M., Coon, H., Dinh, E., Dawson, G., Deutsch, C.K., Dunn, M., Estes, A., Tager-Flusberg, H., Folstein, S., Hepburn, S., Hyman, S., McMahon, W., Minshew, N., Munson, J., Osann, K., Ozonoff, S., Rodier, P., Rogers, S., Sigman, M., Spence, M.A., Stodgell, C.J., Volkmar, F., 2006. Head circumference and height in autism: a study by the Collaborative Program of Excellence in Autism. American Journal of Medical Genetics 140, 2257-74.
  25. Lainhart JE, Piven J, Wzorek M, Landa R, Santangelo SL, Coon H, Folstein S.E., 1997. Macrocephaly in children and adults with autism. Journal of American Academy of Child and Adolescent Psychiatry 36, 282-290.
  26. Miles, J.H., Hadden, L.L, Takahashi, T.N., Hillman, R.E., 2000. Head circumference is an independent clinical finding associated with autism. American Journal of Medical Genetics 95, 339- 50.
  27. Miles, J.H., Takahashi, T.N., Hong, J., Munden, N., Flournoy, N., Braddock, S.R., Martin, R.A., Bocian, M.E., Spence, M.A., Hillman, R.E., Farmer, J.E., 2008. Development and validation of a measure of dysmorphology: useful for autism subgroup classification. American Journal of Medical Genetics 146, 1101-16.
  28. Palmen, S.J., Hulshoff Pol, H.E., Kemner, C., Schnack, H.G., Janssen, J., Kahn, R.S., Van Engeland, H., 2004. Larger brains in medication naive high-functioning subjects with pervasive developmental disorder. Journal of Autism and Developmental Disorders 34, 603-13.
  29. Philip, R.C., Dauvermann, M.R., Whalley, H.C., Baynham, K., Lawrie, S.M., Stanfield, A.C., 2012. A systematic review and meta-analysis of the fMRI investigation of autism spectrum disorders. Neuroscience & Biobehavioral Reviews 36, 901-42.
  30. Piven, J., Arndt, S., Bailey, J., Havercamp, S., Andreasen, N.C., Palmer, P., 1995. An MRI study of brain size in autism. American Journal of Psychiatry 152, 1145-9.
  31. Rojas, D.C., Bawn, S.D., Benkers, T.L., Reite, M.L., Rogers, S.J., 2002. Smaller left hemisphere planum temporale in adults with autistic disorder. Neuroscience Letters 328, 237-40.
  32. Rojas, D.C., Camou, S.L., Reite, M.L., Rogers, S.J., 2005. Planum temporale volume in children and adolescents with autism. Journal of Autism and Developmental Disorders 35, 479-86.
  33. Schumann, C.M., Hamstra, J., Goodlin-Jones, B.L., Lotspeich, L.J., Kwon, H., Buonocore, M.H., Lammers, C.R., Reiss, A.L., Amaral, D.G., 2004. The amygdala is enlarged in children but not adolescents with autism; the hippocampus is enlarged at all ages. Journal of Neuroscience 24, 6392- 401.
  34. Ververi, A., Vargiami, E., Papadopoulou, V., Tryfonas, D., Zafeiriou, D.I., 2012. Clinical and laboratory data in a sample of Greek children with autism spectrum disorders. Journal of Autism and Developmental Disorders 42, 1470-6.
  35. Walsh, P., Elsabbagh, M., Bolton, P., Singh, I., 2011. In search of biomarkers for autism: scientific, social and ethical challenges. Nature Review Neuroscience 12, 603-12.
  36. Webb, S.J., Nalty, T., Munson, J., Brock, C., Abbott, R., Dawson, G., 2007. Rate of head circumference growth as a function of autism diagnosis and history of autistic regression. Journal of Child Neurology 22, 1182-90.
  37. Woodhouse, W., Bailey, A., Rutter, M., Bolton, P., Baird, G., Le Couteur, A., 1996. Head circumference in autism and other pervasive developmental disorders. Journal of Child Psychology & Psychiatry 37, 665-671.

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Authors
Sacco, R., Gabriele, S., & Persico, A. M.
Affiliations
Università Campus Bio-Medico (IT)
Corresponding author
Sacco, Roberto
ORCID
Venue
Psychiatry Research: Neuroimaging
Publisher
Elsevier BV
Published
2015-11
Volume
234
Issue
2
Pages
239-251
ISSN
0925-4927 (ISSN-L)
DOI
10.1016/j.pscychresns.2015.08.016
OpenAlex
W1918697652
Cited by
253
References
9
Citations by year
2026: 11 · 2025: 24 · 2024: 39 · 2023: 22 · 2022: 22 · 2021: 25 · 2020: 33 · 2019: 15 · 2018: 24 · 2017: 23 · 2016: 13
FWCI
1.97
Type
journal article
Language
en
Open access
Licence
Locations
  • Psychiatry Research Neuroimaging (publishedVersion)
  • PubMed (publishedVersion)
  • IRIS UNIMORE (University of Modena and Reggio Emilia) (submittedVersion, cc-by-nc-nd)
  • IRIS Research product catalog (Sapienza University of Rome) (submittedVersion, other-oa)
  • IRIS UNIMORE (University of Modena and Reggio Emilia) (submittedVersion, cc-by)
Funders
  • Italian Ministry for University, Scientific Research and Technology (2006058195, 2008BACT54_002)
  • Italian Ministry of Health (RFPS-2007-5-640174, RF-2011-02350537)
  • Fondazione Gaetano e Mafalda Luce
  • Autism Aid ONLUS
  • Autism Speaks
  • Autism Research Institute
  • European Union (115300)
Topics
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Health Sciences › Medicine › Psychiatry and Mental health › Child Nutrition and Feeding Issues
Keywords
autism spectrum disorder, macrocephaly, brain overgrowth, head circumference, total brain volume, brain growth, endophenotypes, biomarkers, low-functioning autism
MeSH terms
Autism Spectrum Disorder, Brain, Cephalometry, Child, Preschool, Female, Head, Humans, Male, Prevalence, Endophenotypes

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