Introduction
Autism spectrum disorders (ASDs) are neurodevelopmental disorders characterized by an early onset of severe impairment in social interaction, abnormalities in communication, and restricted and stereotyped patterns of behavior and interests. Symptoms usually start before 3 years of age, and studies of children as young as 12 months of age demonstrate that certain behaviors are predictive of autism later in life, indicating that the origin of the disorder lies very early in development (Lawler et al.
2004). One of the earliest signs of abnormality in ASD is abnormal growth of the brain. MRI and postmortem studies have shown children with ASD to have cerebral, cerebellar, and limbic abnormalities (reviewed by Courchesne et al.
2004). The mean brain volume of children with ASD is greater than that of normal children during childhood, with the difference in brain size peaking between 4 and 5 years of age (Courchesne et al.
2001,
2003; Hazlett et al.
2005; Sparks et al.
2002; reviewed in Redcay and Courchesne
2005). In addition, several studies have shown that some areas of the brain are enlarged whereas other are decreased in size (Carper et al.
2002; Courchesne
1997; Courchesne et al.
2001; Hazlett et al.
2005; Sparks et al.
2002; reviewed in Courchesne et al.
2004). However, these studies all involved children with autism who were older than 2 years, probably because of diagnostic uncertainty in children younger than this age (Wiggins et al.
2006; Zwaigenbaum et al.
2009). Diagnostic uncertainty is a major obstacle to understanding the earliest signs of abnormal brain development in these children.
A way to overcome this problem is to measure indices of brain development before the diagnosis is established. In most western countries, head circumference is measured several times during the first year of life in well-baby clinics, to monitor development, and head circumference is an accurate index of brain size in the first years of life (Bartholomeusz et al.
2002). In this way, abnormalities of brain development can be detected early in children later diagnosed with ASD. Most studies measuring head circumference data from birth to ~3 years of age reported, on average, an
increased head circumference in autistic children (Dawson et al.
2007; Dementieva et al.
2005; Elder et al.
2008; Fukumoto et al.
2008; Gillberg and de Souza
2002; Hazlett et al.
2005; Lainhart et al.
1997,
2006; Mills et al.
2007; Webb et al.
2007), although two other studies reported a
normal head circumference in autistic children of the same age (van Daalen et al.
2007; Torrey et al.
2004). However, it is probable that children with ASD have an
atypical growth pattern (Amaral et al.
2008): at birth, children with ASD appear to have a normal or even
decreased head circumference, followed by an
increase
in the rate of growth of head circumference from about 12 months of age (Amaral et al.
2008; Courchesne et al.
2003; Dissanayake et al.
2006; Mraz et al.
2007). Most research findings indicate that head growth abnormalities are present in a proportion of autistic children, both in terms of a larger head circumference and an atypical acceleration of growth.
Measurement of head circumference in relation to height may provide insight into these growth abnormalities, because the increase in head size may be associated with a general increase in growth in children with ASD. Some studies have documented that head circumference is relatively
increased in comparison to height (Dawson et al.
2007; Fukumoto et al.
2008; Lainhart et al.
2006), whereas others have reported that head circumference is
normal or decreased in relation to height (van Daalen et al.
2007; Mraz et al.
2007). Several studies have reported an
increased height and/or weight in ASD (van Daalen et al.
2007; Dissanayake et al.
2006; Fukumoto et al.
2008; Lainhart et al.
1997; Mills et al.
2007; Mraz et al.
2007; Torrey et al.
2004; Webb et al.
2007; Whitely et al.
2004; Xiong et al.
2007), which suggests that growth in general is increased in ASD.
Because growth parameters are often found to be abnormal in ASD and are to a large part genetically determined (Carmichael and McGue
1995; Maes et al.
1997; Silventoinen et al.
2000), growth abnormalities have been proposed as candidate endophenotypes of ASD (Losh et al.
2008). Endophenotypes are subclinical behavioral, physiological, or neuropsychological markers of a disease that are suspected to be more strongly linked to certain genes than the clinical outcomes of the disease (Gottesman and Gould
2003). Endophenotypes may be particularly useful for exploring different pathways leading to a disorder, because homogeneous subgroups of patients sharing an endophenotypic dysfunction would be expected to share certain genetic features. Thus parameters of growth could be used to distinguish subtypes of ASD that are genetically more homogeneous. However, it has also been argued that endophenotypes should be
disorder specific (Skuse
2001). In this case, the question arises whether or not growth abnormalities are specific to ASD or whether they are the non-specific expression of the biological abnormalities that are found in association with several psychiatric disorders (Skuse
2001). This has hardly been investigated. To the best of our knowledge, only one recent study has compared longitudinal growth parameters in children with ASD or developmental problems other than ASD (Webb et al.
2007). They reported that children with ASD had a larger average head circumference at 1–7 months and a larger average height at 1–4 months than children with developmental disabilities. At the age of 10 months, the children with ASD were larger than the developmentally disabled children, having a larger head and a greater height and weight. However, another study failed to find a difference in head circumference at birth between autistic children and children with attention-deficit/hyperactivity disorder (ADHD; Gillberg and de Souza
2002). These discrepant findings and the small sample sizes on which they are based (28 ASD children and 8 children with developmental disabilities in the Webb study) make it important to replicate these findings in a larger sample.
Therefore, the main aim of this study was to determine whether abnormal growth is predominantly associated with ASD or is a more universal finding in children with psychiatric disorders. Growth abnormalities are in no way uniquely associated with ASD, being also found in Canavan’s and tuberous sclerosis. However, the extent to which growth abnormalities are present in other psychiatric disorders has hardly been investigated. We measured head circumference, which reflects brain volume in the first few years of life, and height and weight, to examine whether abnormal growth is specific to the brain/head or generalized to the whole body. Unlike previous studies, we had a relatively large sample (129 ASD and 59 psychiatric controls, PC) and measured the variables of interest several times (N = 9) during the first 1.5 years of life. We also took the effects of prematurity into account by analyzing the findings with and without premature children included.
Discussion
The aims of the current study were to examine whether abnormal early growth is (a) predominantly related to ASD or is generally found in children with psychiatric disorders (psychiatric controls [PC]), and (b) specific to the brain or generalized to the whole body. The first aim may shed light on whether growth parameters could be viable ASD-specific endophenotypes and whether abnormal growth is more broadly associated with developmental pathology.
Results revealed that, overall, the growth of ASD and PC children was more similar than dissimilar: repeated measure ANOVAs did not detect structural group differences in growth parameters, nor in group by growth curve interactions suggestive of significant long-term group differences in growth. This raises doubts about the use of abnormal growth as a marker of ASD pathology, because abnormal growth was not specific to ASD (Skuse
2001). Our findings suggest that growth abnormalities are a non-specific expression of the biological abnormalities found in association with many psychiatric disorders. However, the one previous study that also examined this issue using longitudinal growth data did find differences in growth between ASD and children with developmental disabilities. Webb et al. (
2007) found that children with ASD had a larger head circumference at 1–7 months and were taller at 1–4 months than children with developmental disabilities. At 10 months, the children with ASD were generally larger than the children with developmental disabilities, having a larger head, height, and weight. The discrepancy between our results and those of Webb et al. may be explained by differences in the nature of the psychiatric control groups. Our psychiatric control group mainly consisted of children with psychiatric disorders (such as communication disorder, ADHD, ODD, anxiety disorder, affective disorder, reactive attachment disorder) or disturbances related to early development (such as regulation problems), whereas the few children in the developmental disabilities group (
N = 8) of Webb et al. were selected on the basis of not passing certain developmental milestones (i.e., exhibiting problems in at least 3 of 5 of the following areas: verbal abilities, nonverbal abilities, nonverbal problem solving, motor milestones and adaptive behavior), rather than on the basis of psychiatric dysfunction. One other study that contrasted autistic children with ADHD children found no differences in head circumference at birth (Gillberg and de Souza
2002). Therefore, on the basis of our preliminary findings, differences in growth parameters appear to be a non-specific expressions of the biological abnormalities associated with psychiatric disorders.
However, even though the groups did not differ significantly overall, growth abnormalities might be helpful for creating more homogeneous subgroups of patients, to facilitate gene detection. The most robust finding from our and previous studies is the heterogeneity of growth trajectories. Some patients with ASD may have similar growth trajectories and form an etiologically more homogeneous subgroup. In addition, time-specific t-tests did reveal some subtle differences between the groups. The most apparent difference was that the children with ASD had an increased head circumference relative to height up to 2 months of age, which was not observed in the PC children. This initial disproportionately large head in comparison to height in the first 2 months of life may be important to our understanding of the unique etiological factors underlying ASD and not other psychiatric disorders.
In both groups of children, growth parameters deviated from a straight line through zero (representing a growth curve completely in conformity with population means), but the shape of the growth curve was not the same for all the parameters.
Head circumference showed a predominantly cubic growth curve, whereby the head circumference tended to be smaller than the norm at birth and normalized later. This is consistent with some previous studies documenting a decreased head circumference at birth in ASD (Courchesne et al.
2003; Dissanayake et al.
2006; Mraz et al.
2007). Nevertheless, the head circumference did not show an abnormal accelerated growth and the proportion of children with macrocephaly was not higher or lower than normal, in contrast to some previous ASD studies (Courchesne et al.
2003; Dawson et al.
2007; Dementieva et al.
2005; Gillberg and de Souza
2002; Lainhart et al.
1997). Our findings suggest that the pattern of head circumference development was in the main normal. However, the growth curve of
head circumference in relation to height indicated that ASD children had a larger head relative to their length at birth, which then showed an abnormal growth deceleration, resulting in a head circumference that was small relative to height over time, as shown previously (van Daalen et al.
2007). Notwithstanding these findings, the differences were very small (−0.25
z score) and given that population growth curves are constructed from thousands of individuals, it is difficult to say whether these findings are typical. With respect to
general body growth, the children with ASD tended to be smaller than normal at birth (possibly due to a higher than normal prevalence of prenatal and perinatal risk factors in our ASD sample [unpublished data]), yet showed an abnormal growth acceleration, becoming taller than normal children, consistent with earlier reports of abnormally increased height (van Daalen et al.
2007; Fukumoto et al.
2008; Torrey et al.
2004). At the same time, their weight did not increase proportionally, making these children on average taller and thinner than normal children. Thus both ASD and PC children grew differently from the population norms. In general, these children were smaller at birth, but were significantly taller at about 1.5 years. Head circumference and body weight did not match this ‘growth spurt’—both parameters lagged somewhat behind the growth in height, making these children as a group somewhat taller, thinner, and with proportionally smaller heads than age- and sex-matched peers. The etiology of these growth abnormalities may be genetic, environmental (such as maternal substance abuse, poor nutrition, intrauterine infections, etc.), or a combination of both. While we do not want to suggest that the growth abnormalities of children with ASD or other psychiatric disorders are solely genetically based, we believe that shared genetic factors influence psychiatric functioning and growth in these children.
Our results should be interpreted in the context of the limitations of this pilot study. Most importantly, the PC group was very heterogeneous. A more homogeneous control group, such as children with mental retardation of a specific type, might have revealed greater differences in growth. We repeated the analyses, comparing children with communication disorders (
N = 16) and ADHD/ODD (
N = 16) with the children with ASD. Except for a main group difference in head circumference between the ASD and ADHD/ODD group (
p = .05), the head circumference of the children with ASD was normal, whereas that of the children with ADHD/ODD was smaller than normal, no other main effects or interaction effects emerged between the groups (results available upon request). Thus, given that children with ADHD are also known to show early growth abnormalities (although often in relation to risk factors such as prematurity, smoking, and hypertension), our findings suggest that growth parameters are related to psychiatric dysfunctioning in general. Secondly, it is likely that a proportion of our ASD sample suffered from one or more comorbid psychiatric conditions, such as ADHD. However, this is probably also true of other samples of young children with ASD. Our PC group had been thoroughly screened and found to be negative for ASD. The crucial difference between the two groups is the presence/absence of ASD, which makes comparison of the two groups viable. A related limitation is the young age at which our subjects were diagnosed, so that autism, particularly Asperger’s disorder and high functioning autism, could not be excluded with certainty in the children in the PC group and could only be confirmed in the ASD group as they became older. We are in the process of investigating this. Fourthly, the IQ differences between the ASD and PC groups could have influenced the results. However, even though IQ was strongly related to several growth parameters, including IQ as a covariate in the analyses did not influence the lack of group differences or group by growth curve interactions. Socioeconomic status, which could influence growth, was not taken in consideration. However, differences in socioeconomic status are not large in the Netherlands, and Lainhart et al. (
2006) did not find socioeconomic status to be associated with head size in autistic children. Lastly, it would have been valuable to have included a third group of control children to exclude the possibility of specific cohort effects, but this would not have influenced the findings of similar abnormal growth in ASD and PC children.
In conclusion, our study showed that growth abnormalities appear to be a non-specific expression of biological abnormalities found in several psychiatric disorders. The growth of both ASD and PC children differed from population norms. Generally, these children were smaller at birth, but after a period of abnormal growth acceleration, they were significantly taller than normative samples of children at about 1.5 years. Head circumference and body weight did not match this ‘growth spurt’ in height, so that these children as a group were somewhat taller, thinner, and with proportionally smaller heads than age- and sex-matched peers. Although head circumference, weight, and height did not distinguish between the ASD group and the PC group, the growth trajectories of the two groups were heterogeneous.
We aim to replicate and extend these findings by examining whether head circumference differs between ASD probands, genetically related siblings with ADHD but without ASD, and a group of genetically unrelated children with ADHD but no ASD relatives. This may help answer the question whether growth abnormalities are predominantly associated with ASD (in which case the first group will show on average more abnormalities than the other two groups), or associated with more general heritable/familial risk factors in ASD families (in which case the ASD probands and ADHD-affected siblings will show on average more abnormalities than the genetically unrelated ADHD children), or associated with psychiatric problems in general (in which case the three groups will not differ substantially from each other, but will differ from population norms).