Interactive Autism Network at Kennedy Krieger Institute
Date Published: September 9, 2013
For years researchers have said children with autism are more likely to have large heads, a phenomenon they attributed to "early brain overgrowth."
Armin Raznahan M.D., Ph.D., repeated that scientific theory himself. "Like everyone else, I used the line that 'autism is associated with early brain overgrowth,'" said Dr. Raznahan, a scientist at the National Institute of Mental Health.
But now he and other researchers – including some using data from Simons Simplex Collection families – are questioning assumptions about brain overgrowth and autism, especially how common it is. Their stories spotlight the important ways science reconsiders evidence in the search for answers.
Role of Growth Charts
Many studies have found that from a tenth to a third of children with autism have unusually large heads.1, 2 Scientists drew that conclusion by comparing the youngsters' head-circumference measurements to American or international charts that plot normal growth by age and gender. At a typical "well-baby" exam, a doctor or nurse will measure a baby's head, weight and length, and record those numbers on a chart showing percentiles.
An excessively large head could point to serious problems such as fluid in the brain. However, in the children with autism, scientists believed a bigger head size was related to brain size. They theorized that the youngsters were experiencing an overgrowth of brain matter during their first year of life, and wondered if the overgrowth was an early warning sign of autism.
Of course, they assumed the growth charts were correct. But what if they weren't?
Two recent studies addressed this very concern. One, which appeared in the prestigious journal Pediatrics, examined the head circumference measurements of more than 75,000 children in a large U.S. primary care network. Researchers found that two growth charts, one from the U.S. Centers for Disease Control (CDC) and the other from the World Health Organization (WHO), identified too many of the children as having abnormally large heads. In other words, head sizes overall were larger than the charts predicted.3
The medical term for an abnormally big head is "macrocephaly," from the Greek words for large and head. Macrocephaly can be a sign of brain and genetic conditions, although a person can have macrocephaly and be otherwise normal.4
Compared to What? Examining Autism Research
Most research connecting macrocephaly to autism spectrum disorder (ASD) relied upon standardized growth charts, and Dr. Raznahan's research team decided to examine 34 such studies. "The notion of the big-headness in autism has massively influenced autism neuroscience," he said, so the topic warranted further investigation.
His findings "shocked" even him: the growth charts used in many of the studies made it appear that more children had abnormally large heads than really did. All together, the studies reported an average macrocephaly rate of 14 percent in children with ASD. But when his team excluded studies that relied upon certain growth charts, the average rate fell to 4 percent.5 That's not far from the 3 percent rate of macrocephaly in the general population.2
The team found 13 head-size studies that did not rely solely on growth chart standards. Of those, slightly more than half found evidence of head enlargement in ASD, while the others did not.5
Those conclusions do not mean that head size is unimportant in autism, however. "Our study doesn't contradict the finding that there is a subgroup of children with autism with unusually large heads," Dr. Raznahan explained. However, the overgrowth appears to occur later in early childhood that previous studies found, and to be more subtle than the dramatic picture painted in some earlier reports.
A Novel Formula for Judging Head Sizes
In a separate study, a group of researchers approached the issue of head size from a different angle. Using data from families in the Simons Simplex Collection (SSC), the research team compared head sizes of children with autism to those of their unaffected siblings and parents.
The researchers found a high rate of macrocephaly among the SSC families when they compared them to standardized head-circumference charts. In fact, almost 15 percent of the children with autism, 13 percent of the fathers, 20 percent of the mothers and 13 percent of the siblings had large heads for their gender and age, based on such charts.1
However, the team created a formula for considering other factors that can affect the size of a person's head. Head size, like other physical attributes, may be affected by the genes we inherit from our parents, along with height, weight and ethnic ancestry.1 When those factors were considered, the team found very few people whose heads were unexplainably large – just 3.6 percent of the children with autism.
They did find one very small but intriguing difference. The SSC children with ASD had an average head size that was 2 millimeters larger than their unaffected brothers and sisters. That's about the width across of an apple stem or the metal tip of a ballpoint pen.
They did find that children whose heads were significantly larger or smaller than expected, given their genetic potential, had lower intelligence.
Genes Influence Head Size
"Having autism doesn't necessary mean having a big head. Having autism is less important to head circumference than other factors we examined like height, weight and genetic ancestry," said researcher Soo-Jeong Kim, a child psychiatrist at Seattle Children's Research Institute.
Their research paper calls for doctors to consider such factors when determining if a child's head size is truly abnormal. Growth charts "will classify individuals as macrocephalic far more often that is clinically appropriate" and miss other people whose heads are larger than their genes would otherwise predict.1
Spokespeople for the CDC said they do not comment on research by scientists outside that federal agency, so they had no response to the head circumference studies. CDC recommends that American pediatricians use WHO growth charts for children from birth to age 2, rather than its own. The WHO charts track the growth of babies in different countries who are breastfed for 12 months.6 According to the study in Pediatrics, using either the WHO or CDC charts in older infants could result in some children being misidentified with macrocephaly.
- Chaste, P., Klei, L., Sanders, S.J., Murtha, M.T., Hus, V., Lowe, J.K., Willsey, A.J., Moreno-De-Luca, D., Yu, T.W., Fombonne, E., Geschwind, D., Grice, D.E., Ledbetter, D.H., Lord, C., Mane, S.M., Lese Martin, C., Martin, D.M., Morrow, E.M., Walsh, C.A., Sutcliffe, J.S., State, M.W., Devlin, B., Cook, E.H. Jr & Kim, S-J. (2013) Adjusting Head Circumference for Covariates in Autism: Clinical Correlates of a Highly Heritable Continuous Trait. Biol Psychiatry. 2013 Jun 6. pii: S0006-3223(13)00389-2. View abstract.
- Dementieva, Y.A., Vance, D.D., Donnelly, S.L., Elston, L.A., Wolpert, C.M., Ravan, S.A., DeLong, G.R., Abramson, R.K., Wright, H.H. & Cuccaro, M.L. (2005) Accelerated head growth in early development of individuals with autism. Pediatr Neurol. 2005 Feb;32(2):102-8. View abstract.
- Daymont, C., Hwang, W.T., Feudtner, C. & Rubin, D. (2010) Head-circumference distribution in a large primary care network differs from CDC and WHO curves. Pediatrics. 2010 Oct;126(4):e836-42. View abstract.
- Menounou, A. (2011) Head Size: is it important? Advances in Clinical Neuroscience and Rehabilitation. May/June 2011. Volume 11 Number 2. Retrieved from http://www.acnr.co.uk.
- Raznahan, A., Wallace, G.L., Antezana, L., Greenstein, D., Lenroot, R., Thurm, A., Gozzi, M., Spence, S., Martin, A., Swedo, S.E. & Giedd, J.N. (2013) Compared to What? Early Brain Overgrowth in Autism and the Perils of Population Norms. Biol Psychiatry. 2013 May 23. pii: S0006-3223(13)00303-X. View abstract.
- Centers for Disease Control and Prevention Morbidity and Mortality Weekly Report. (September 10, 2010) Use of World Health Organization and CDC Growth Charts for Children Aged 0?59 Months in the United States. Retrieved from http://www.cdc.gov/.