Context Autism most commonly appears by 2 to 3 years of life, at which time
the brain is already abnormally large. This raises the possibility that brain
overgrowth begins much earlier, perhaps before the first clinically noticeable
Objectives To determine whether pathological brain overgrowth precedes the first
clinical signs of autism spectrum disorder (ASD) and whether the rate of overgrowth
during the first year is related to neuroanatomical and clinical outcome in
Design, Setting, and Participants Head circumference (HC), body length, and body weight measurements during
the first year were obtained from the medical records of 48 children with
ASD aged 2 to 5 years who had participated in magnetic resonance imaging studies.
Of these children, 15 (longitudinal group) had measurements at 4 periods during
infancy: birth, 1 to 2 months, 3 to 5 months, and 6 to 14 months; and 33 (partial
HC data group) had measurements at birth and 6 to 14 months (n = 7), and at
birth only (n = 28).
Main Outcome Measures Age-related changes in infants with ASD who had multiple-age measurements,
and the relationship of these changes to brain anatomy and clinical and diagnostic
outcome at 2 to 5 years were evaluated by using 2 nationally recognized normative
databases: cross-sectional normative data from a national survey and longitudinal
data of individual growth.
Results Compared with normative data of healthy infants, birth HC in infants
with ASD was significantly smaller (z = –0.66, P<.001); after birth, HC increased 1.67 SDs and mean
HC was at the 84th percentile by 6 to 14 months. Birth HC was related to cerebellar
gray matter volume at 2 to 5 years, although the excessive increase in HC
between birth and 6 to 14 months was related to greater cerebral cortex volume
at 2 to 5 years. Within the ASD group, every child with autistic disorder
had a greater increase in HC between birth and 6 to 14 months (mean [SD],
2.19 [0.98]) than infants with pervasive developmental disorder-not otherwise
specified (0.58 [0.35]). Only 6% of the individual healthy infants in the
longitudinal data showed accelerated HC growth trajectories (>2.0 SDs) from
birth to 6 to 14 months; 59% of infants with autistic disorder showed these
accelerated growth trajectories.
Conclusions The clinical onset of autism appears to be preceded by 2 phases of brain
growth abnormality: a reduced head size at birth and a sudden and excessive
increase in head size between 1 to 2 months and 6 to 14 months. Abnormally
accelerated rate of growth may serve as an early warning signal of risk for
Behavioral signs and symptoms during the second and third years of life,
including delayed speech, unusual social and emotional reactions, and poor
attention to and exploration of the environment, raise warnings that a child
might have autism.1-5
Autism is a neurobiological disorder,6-8 and
neurobiological abnormalities must necessarily precede the first behavioral
expressions of the disorder. However, such neurobiological early warning signs
have not yet been discovered for autism. Knowledge of such signs could lead
to objective, quantifiable, and reliable clinical tests for autism; earlier
identification and intervention; and eventually insight into the original
causes and/or mechanisms present at the earliest stages of the disorder.
One neurobiological abnormality, increased brain volume, is detectable
at an age when clinical signs are becoming apparent.9 Ninety
percent of 2- and 3-year-old children had brain volumes larger than the healthy
average,9 as well as abnormally large head
circumferences (HCs).10 Another study reported
that brain size in 4-year-old children with autism exceeded the healthy average.11 Excessive brain size was primarily due to increased
white matter volumes in the cerebellum and cerebrum9 and
increased gray matter volume in the cerebrum, within which frontal lobes were
most abnormal.12 A discriminant function analysis
revealed that 95% of 2- to 5-year-old children with autism were separately
classified from children without autism based on cerebral and cerebellar magnetic
resonance imaging (MRI) volume measurements (N.A., unpublished data, March
Whether pathological brain overgrowth precedes, co-occurs with, or follows
the onset of the first clinical behavioral signs of autism is unknown. Given
that HC throughout the first years of life is an accurate index of brain size,13-15 an important observation
is that birth HCs in children with autism are not abnormally large.9,16-18 Because
excessive brain size is not present at birth but is present by 2 to 3 years,9 this overgrowth must begin sometime between these
In this study, we aimed to determine whether pathological brain overgrowth
precedes the first behavioral expressions of autism and whether abnormal growth
trajectories predict the neuroanatomical and clinical outcomes of children
with autism. To establish relationships between growth during infancy and
later neuroanatomical outcome, we included all 2- to 5-year-old children with
an autism spectrum disorder (ASD), which included autistic disorder (AD, more
severe form of ASD) and pervasive developmental disorder-not otherwise specified
(PDD-NOS, milder form of ASD), on whom we had quantitative MRI measurements
(R.C., unpublished data, May 2003; N.A., unpublished data, March 2003)9,10,12,19 and
requested birth and first year HC measurements from each child's medical records.
Due to variability in procedures across pediatricians, the exact ages at which
HC was measured varied from patient to patient. Because medical records for
some patients were unavailable and others did not include regular HC measurements,
our final sample size was about half that of our original MRI study sample.
Despite the confines imposed by such a design, our study had a number
of significant strengths. First, the critical HC measurement was obtained
in an unbiased fashion. The measurements were recorded by medical staff in
ordinary clinics, not clinics specializing in suspected developmental disorders.
These individuals were unaware that the infants would develop an ASD. The
measurements were recorded by different individuals, which eliminates the
possibility of any systematic error in measurement biasing the results. The
methods and individuals involved in acquiring infant HC and developmental
outcome brain size on MRI were also completely independent of each other.
Second, our study is a contemporary sample of children with ASD now being
observed in clinics. Third, our sample was diagnosed with rigorous contemporary
methodology by using a prospective, longitudinal diagnostic follow-up design.
Full descriptions of this design have been published previously.9 By
using a sample of children with ASD on whom we had MRI data, we were in the
unique position to examine relationships between HC changes during the first
year and MRI-based measurements of the brain at a later developmental age,
namely 2 to 5 years.
To establish at what ages HC in infants with ASD differs from that in
healthy infants, we compared our HC measurements of children with ASD to the
Centers for Disease Control and Prevention (CDC) growth charts of the United
States.20 To determine how often healthy developing
infants show extreme growth deviations in HC during the first year and whether
longitudinal growth trajectories differ between individual healthy infants
and those with ASD, we compared our longitudinal HC measurements from infants
with ASD to those available from a nationally recognized, contemporary cohort
of healthy infants.21
The study was approved by the institutional review board of San Diego
Children's Hospital Research Center. All participants were recruited from
community advertisements and referrals, and informed consent was obtained
from the parents of the children.
A total of 48 children with ASD aged 2 to 5 years participated; 92%
of them were white. Each had been a participant in previous MRI studies reporting
age-related changes in the brain in autism (R.C., unpublished data, May 2003;
N.A., unpublished data, March 2003).9,12,19
The diagnosis of ASD was based on multiple criteria as previously described,9 resulting in a conservative selection of participants
that would be expected to lead to better agreement than clinical diagnosis
alone.22 All children met inclusionary criteria
for the diagnosis of AD or PDD-NOS based on the Diagnostic
and Statistical Manual of Mental Disorders, Fourth Edition23; the Autism Diagnostic Interview24 or
the Autism Diagnostic Interview–Revised25;
and the Autism Diagnostic Observation Schedule.26 For
1 child, the Autism Diagnostic Observation Schedule was not completed, but
a diagnosis of AD was made based on clinical observation, the Autism Diagnostic
Interview–Revised, and collateral records. Of the total 48 children
with ASD, 40 met criteria for AD and 8 for PDD-NOS. Diagnostic and IQ data
at the age of MRI scan (ages 2-5 years) are given in Table 1. All patients were full term at birth and negative for fragile-X,
except 9 who did not receive this test. Patients with concurrent medical conditions
Physicians, clinics, and hospitals involved in the treatment of each
of the 48 children with ASD were contacted to obtain all available medical
records containing clinical HC, length, and weight measurements. Of the 48
patients with ASD, 15 (12 males and 3 females) had pediatric HC measurements
at 4 age periods: birth, 1 to 2 months (mean [SD] age, 1.6 [0.5] months),
3 to 5 months (4.2 [0.6] months), and 6 to 14 months (10.6 [2.6] months) and
were termed the longitudinal group. The remaining 33 children (29 males and
4 females) were termed the partial HC data group because they had HC measurements
at birth and 6 to 14 months (n = 7) and at birth only (n = 28). Also, 2 did
not have a birth HC measurement but did have an HC measurement at 2 weeks
Birth HC, body length, and body weight did not significantly differ
between the longitudinal and partial HC data groups (Table 2). However, birth HC was significantly smaller in both ASD
groups compared with the CDC average of healthy infants (longitudinal group: z = –0.66, t14=
–3.94, P = .001; partial HC data group: z = –0.41, t32 =
–3.07, P = .004). In contrast, neither length
nor weight of all infants were smaller than the CDC averages of healthy infants.
Clinical and MRI Characteristics of Longitudinal and Partial HC Data
To further determine whether those infants who had their head frequently
measured by their pediatrician differed from those infants who did not, we
compared clinical and MRI characteristics of the longitudinal and partial
HC data groups (Table 2 and Table 3). t Tests
revealed that there were no significant group differences with any of these
clinical or MRI variables.
Statistical Analyses and Normative Databases
Statistical analyses were carried out by using SPSS statistical software
version 10 (SPSS Inc, Chicago, Ill); P≤.05 was
considered statistically significant. Head circumference, length, and weight
measurements were normalized across sex and age by converting to z scores based on the CDC averages of healthy infants.20 Head
circumference data from 51 infants born between 1980 and 2001 from the Fels
Longitudinal Study21 were made available to
us for comparison with the ASD sample. The infants from the Fels Longitudinal
Study included 26 males and 25 females and were a subset of the more extensive
Fels Longitudinal Study sample. All were white infants recruited from middle-class
families in southwestern Ohio.
HC Growth During the First Year
The Longitudinal Group vs CDC Data. To identify when during the first year HC in infants with ASD deviated
significantly from averages of healthy infants, data from the longitudinal
group were compared with the CDC data. A repeated measures analysis of variance
of HC z scores at birth, 1 to 2 months, 3 to 5 months,
and 6 to 14 months showed a statistically significant effect of age (F3,42 = 16.87, P<.001). This age-related
change was because of a sudden increase in HC measurement beginning after
1 to 2 months (Figure 1). Follow-up
analyses showed that HC was significantly smaller than healthy measurements
at birth (z = –0.66, 25th percentile). However,
between 1 to 2 months and 3 to 5 months, HC increased by 0.66 SDs to a mean z score of 0.18; between 3 to 5 months and 6 to 14 months,
HC increased by 0.83 SDs to a mean z score of 1.01.
Between birth and 6 to 14 months of age, the mean HC of infants with ASD increased
from the 25th to the 84th percentile, an increase of 1.67 SDs.
Body length and weight at birth and 1 to 2 months were not significantly
smaller than averages of healthy infants, and at 3 to 5 months and 6 to 14
months were not significantly larger than averages of healthy infants; therefore,
none of the significant HC deviations from healthy averages in the infants
were explained by differences in body length and body weight at any of the
4 age groups.
Nine of these 15 longitudinal group infants also had at least 1 pediatric
HC measurement between 15 and 28 months (mean [SD], 19.22 [4.38]). Although
HC at this age range was significantly greater than the CDC data of healthy
infants (mean [SD] z score, 1.10 [1.12], 86th percentile),
it was not a statistically significant increase over the mean z score for HC at 6 to 14 months.
Longitudinal Changes in Infants With ASD vs Individual Fels Longitudinal
Study Infants. Of the 51 Fels Longitudinal Study infants, only 6 had pediatric HC measurements
at the same 4 age periods as the longitudinal group; therefore, a within-participant
longitudinal comparison to our longitudinal group infants at 4 age periods
was not possible. However, 31 of the Fels Longitudinal Study infants had 1
HC measurement at birth to 2 months (mean [SD], 0.4 [0.6] months) and a second
at 6 to 14 months (10.1 [1.5] months). Seven infants with ASD from the partial
HC data group who had both birth and 6 to 14 month HC measurements were added
to the longitudinal sample, providing a total of 22 infants with ASD with
HC measurements at 2 similar age periods, namely, birth and 6 to 14 months
(10.3 [2.7] months). The HC measurements from the 31 Fels Longitudinal Study
infants were converted to z scores based on the CDC
averages of healthy infants; however, the birth HC in the CDC averages of
healthy infants were based entirely on the Fels Longitudinal Study data set,
and the CDC averages for HC at all other age periods were based on a national
survey collected separately from and independently of the Fels Longitudinal
Comparison of the 31 Fels Longitudinal Study infants and the 22 infants
with ASD showed that the increase in HC between birth and 6 to 14 months was
significantly greater for the infants with ASD (ASD vs Fels Longitudinal Study
infants: mean (SD) z score, 1.82 [1.11] vs 0.76 [0.74];
t51 = 4.18; P<.001).
Measurements at Birth vs Later Clinical Indices and MRI Measurements
A priori hypotheses9 suggested that the
magnitude of brain changes of abnormal nature during infancy in autism might
be related to later clinical and brain size outcome. To test this hypothesis,
the 2 main HC effects (ie, reduced birth HC and the HC increase during infancy)
were used. To increase statistical power, the infants with ASD (n = 22) who
had both birth and 6 to 14 month HC measurements were examined.
Clinical Indices. A median split was performed on the birth HC of these infants, resulting
in 1 subgroup with a mean (SD) birth HC z score of
–1.27 (0.44) (10th percentile) and another with a z score of 0.07 (0.46) (53rd percentile). A median split was also performed
on the birth to 6 to 14 month HC increase in these infants, resulting in 1
subgroup with an HC increase of 0.94 (0.48) (73rd percentile) and another
with an HC increase of 2.71 (0.79) (97th percentile). Among patients with
functional language, smaller birth HC was associated with a worse verbal score
on the Autism Diagnostic Interview (19.6 vs 14.4; t10 = 2.81; P = .02). A greater increase in HC measurement during infancy
was associated with a significantly worse score on the stereotyped and repetitive
behaviors scale of the Autism Diagnostic Observation Schedule (3.6 vs 2.0;
t20= –2.21; P = .04); a strong trend
toward a later age of onset for first words (44 vs 30 months; t15 =
–2.00; P = .06); and a trend toward a higher
score on the Childhood Autism Rating Scale,27 a
clinical index of the severity of autistic symptoms (38 vs 31; t20 =
–1.93; P = .07).
MRI Outcome.Table 4 shows correlations
between HC measurements in the first year and quantitative MRI measurements
of the brain at 2 to 5 years. Only male infants were considered in analyses
of MRI outcome measurement. Smaller birth HC was significantly correlated
with smaller cerebellar gray matter volumes in childhood after controlling
for age at MRI (r = 0.53; df =
14; P = .04); a strong trend was observed for cerebellar
white matter volume (r = 0.49; df = 14; P = .06). Birth HC was not significantly
correlated with any cerebral measures. Conversely, a greater increase in HC
during the first year was significantly correlated with greater cerebral gray
matter, whole brain gray matter, and whole brain volumes (all correlations r≥0.48; df = 15; P≤.03) but not with any white matter measures or cerebellar measures
(Table 4). Additionally, HC measurements
at 6 to 14 months was significantly correlated with greater cerebral gray
matter (Figure 2), cerebral white
matter, whole brain gray matter, whole brain white matter, whole brain volumes
(all correlations r≥0.54; df = 15; P≤.03), and cerebellar gray matter
(r = 0.54; df = 14; P = .05) (Table 4).
AD vs PDD-NOS Outcome. Among the 22 infants with ASD with both birth and 6 to 14 month HC measurements,
17 were diagnosed with AD and 5 with PDD-NOS. Birth HC measurements of mean
(SD) z score were not significantly different between
the 2 groups (AD: –0.55 [0.83], 29th percentile; PDD-NOS: –0.48
[0.83], 32nd percentile). However, there was a striking difference in the
HC measurement increase because from birth to 6 to 14 months, the infants
with AD increased 2.19 (0.98), reaching the 95th percentile, while the infants
with PDD-NOS increased only 0.58 (0.35), reaching only the 54th percentile
Furthermore, for 71% of the infants with AD, the magnitude of the increase
was greater than 1.5 SDs with 59% of the infants having increases between
2.0 and 4.3 SDs. None of the infants with PDD-NOS had increases more than
1.0 SDs. Among the 31 healthy Fels Longitudinal Study infants in our analyses,
only 9% had increases of more than 1.5 SDs, with 6% having increases of more
than 2.0 SDs. As a result of the large increase in HC by 6 to 14 months, 15
(88%) of the 17 infants with AD had HC values that exceeded the 87th percentile
(z≥1.15) and 9 (53%) of 17 were at or above the
97th percentile (z≥1.87).
Figure 4 shows the growth
curve for the male infants with AD (14 of the total 17) relative to the CDC
10th, 50th, and 90th percentile curves for healthy male infants; all HC measurements
at birth, 1 to 2 months, 3 to 5 months, and 6 to 14 months from these 14 male
infants with AD were used to calculate the best fit curve.
This is the first study to our knowledge to find a potential early warning
neurobiological sign for autism and to link it to a later brain abnormality.
Specifically, we found a rapid and excessive increase in HC measurements,
and therefore, presumably, brain size, beginning several months after birth.
This abnormally accelerated rate of increase in HC measurements in infants
with ASD was evident in comparisons to 2 nationally recognized normative databases,
one a national cross-sectional survey and the other a longitudinal study of
growth patterns in healthy infants. In our study, head size increased from
the 25th percentile based on the CDC averages of healthy infants to the 84th
percentile in 6 to 14 months. This excessive increase occurred well before
the typical onset of clinical behavioral symptoms. Moreover, this increase
by the end of the first year was strongly correlated with greater cerebral
and cerebellar volumes by 2 to 5 years of age. These results suggest that
growth dysregulation in 2 major cortices and underlying white matter in the
brain underlies the increase in HC.
The cellular bases of the brain volume increases remains to be determined
and could reflect any of a number of possibilities, including excessive numbers
or rates of growth of neurons and/or glial cells, excessive numbers of minicolumns,
excessive and premature expansion of dendritic and axonal arbors, excessive
numbers of axonal connections, and/or premature myelination. The causes also
remain to be identified and could reflect an abnormal acceleration of postnatal
growth processes or a failure of late prenatal and early postnatal regressive
processes. The brain volume increases could also reflect either aberrant compensatory
responses to adverse prenatal conditions or deviant biological mechanisms
that are first expressed in early postnatal life. Events and conditions, such
as measles, mumps, and rubella vaccinations, childhood exposure to environmental
toxins or pathogens, or unusual gastrointestinal or allergic reactions to
food, that occur after the overgrowth are not logically plausible as causes.
Although some may argue that such later occurring events might be important
as aggravating factors, the key question remains—what triggers the abnormal
brain overgrowth in the first months of life initially?
In our study, this overgrowth was also a reliable neurobiological phenomenon
among the children with AD within our sample of infants with ASD. Among the
infants who have the more severe form of autism, 71% showed increases during
their first year of more than 1.5 SDs, with 59% showing increases between
2.0 and 4.3 SDs. Such high percentages were not observed in the typically
developing infants in the Fels Longitudinal Study sample. Our sample of infants
with ASD also included a very small number of children with PDD-NOS, a milder
condition of autism. In contrast with the children with AD, all of the children
with PDD-NOS showed small increases, in which their HC measurement increased
from less than the 50th percentile up to the 54th percentile. This contrast
between infants with the more and less severe forms of autism is compatible
with our previous hypothesis9 that an earlier
onset, faster rate, and longer period of excessive brain growth might be associated
with poorer outcome (eg, AD), and the converse, later onset, slower rate,
and shorter period of excessive growth, might be associated with a better
outcome (eg, PDD-NOS). Larger samples of infants with ASD will be needed to
further support this clinically and neurobiologically relevant hypothesis.
Our analyses of the Fels Longitudinal Study data suggest that although
extreme HC measurement increases may occur occasionally in healthy developing
infants, they are much less common (6% of cases) than in infants later diagnosed
with AD (59% of cases). Aberrantly excessive head size in infants may also
occur in disorders, such as hydrocephalus, benign megalencepaly, tumor, and
subdural hematoma; therefore, it is important for physicians to rule out these
types of conditions via physical, imaging, and biological examinations. Although
an abnormally large increase in HC in an infant cannot be viewed as a certain
and unique marker of autism, it nonetheless does appear to be an important
signal that an infant is at significantly heightened risk for the disorder.
If further research verifies this result, it may become an important observation
in the clinic alerting the physician to the need for follow-up tests for possible
autism. Further research may identify a combination of biological (eg, biochemical,
MRI, genetic) and behavioral signs that together compose an accurate and early
diagnostic prognosis, which might make it possible to begin treatment 2 or
3 years earlier than is now commonly the protocol. However, as demonstrated
by some animal models (eg, monocular deprivation)32 and
human disorders (eg, phenylketonuria)33 of
brain development, a substantially improved outcome can result from appropriate
interventions begun before aberrant neural circuit configuration and function
have been irreversibly established. Similarily, identifying novel early treatments
for autism should result in a better outcome than is currently possible.
There appear to be at least 4 phases of brain growth in autism. The
first phase involves a slight undergrowth of the prenatal brain because, at
birth, the average HC measurement is at the 25th percentile. This is not due
to overall decreases in prenatal body growth because body length and weight
at birth are not less than the values of healthy infants. Although the brain
volume decrease at birth is small, it coincides with speculations about prenatal
neural defects inferred from adult autistic postmortem brains.6,34-40 The
second growth phase involves the rapid and large overgrowth within the first
year described in the current study. The third phase appears to last about
2 to 4 years, during which the overall rate of brain growth slows, so that
by ages 4 to 5 years, brain size in autism reaches its near maximum.9 Importantly, this maximum brain size in young children
with autism (approximately 1350 mL) is similar to that achieved by healthy
children (approximately 1360 mL), but about 8 years too soon.9 The
fourth phase involves a gradual decline in overall brain size and extends
from middle or late childhood through to adulthood. By adolescence and adulthood,
brain size in autism is not significantly different from the healthy average.9,10
A new MRI study of 8- to 46-year-old patients with autism and healthy
patients has confirmed that the brain in autism is only slightly larger than
average size by late childhood, and that by adolescence and adulthood, it
does not differ significantly in size.41 The
evidence indicates, therefore, that autism is a disorder involving a transient
period of postnatal pathologically rapid brain growth. Only during the very
first years of postnatal life in autism is the brain abnormally enlarged and
not before (eg, at birth) or after (eg, adolescence and adulthood). There
are exceptions to this rule. Of the 48 infants with ASD in our study, 2 had
birth HC measurements at more than the 80th percentile. There also are rare
cases of autism in which brain volumes of infants exceed all healthy patients
of all age groups.9,42
This early, yet transient, period of brain overgrowth must be an important
factor in causing the emergence of autistic behavior because it occurs at
the beginning of an important period of developmental neuroplasticity and
learning. Evidence from studies of developmental neuroplasticity32,43-49 leads
to the conclusion that the developing human brain is designed to benefit from
an extended period of experience-guided growth. The long period of plasticity
provides the opportunity for a multitude of experiences in the form of sensations,
emotions, thoughts, and actions to direct axonal and dendritic growth, and
to create, reinforce, or eliminate synapses as needed. Such extended experience-guided
growth inevitably leads to the emergence of refined higher order neurobehavioral
functions, such as those cognitive, emotional, linguistic, and motor skills
necessary for understanding and actively socially engaging others. In autism,
the brain may compress for a short time an amount of overall growth that takes
many years in typically developing children to unfold.9,12,50-54 Thus,
there is aberrantly rapid and disordered growth without guidance that produces
in too short a time too many connections that may not be adaptive. Faced with
the neural noise that would be the result of such rapidly changing aberrant
connections, the infant would lose the ability to make sense of its world
and withdraw. Not until later, when the excessive growth rate slows, would
the now autistic child have a chance to use experience-guided processes to
select whatever connections might still be useful and to eliminate those that
are not. By that time, however, the extended period of plasticity that allows
the exquisite and graceful complexity of the human brain to emerge will have
There is large literature emphasizing the heterogeneity, particularly
of behavioral outcome, in autism. Yet, in the current study, 76% of the children
with AD had HC measurements below the 50th percentile at birth, 88% showed
early postnatal brain overgrowth with HC measurements exceeding the 87th percentile
by 6 to 14 months, and 59% showed extreme (>2.0 SD) increases during the first
year. In other studies of autism, 95% of cases had elevated blood levels of
brain growth factors at birth55; more than
95% of cases have cerebellar pathology6,35-37,39;
more than 95% of 2- to 5-year-old patients were correctly distinguished from
healthy measurements on the basis of only cerebellar and cerebral white matter
volumes (N.A., unpublished data, March 2003); and 100% of cases have increased
neuron packing density in limbic structures.36 Such
biological consistencies, along with the relatively uniform onset age and
excessive rate of brain growth reported in the current study, raise the interesting
possibility that some biological factors leading to autism might be similar
across the majority of patients. Perhaps the outcome heterogeneity might have
more to do with the multitude of genetic and nongenetic background factors
that differ between patients.
In conclusion, our study found evidence of neonatal brain undergrowth
followed by rapid and excessive postnatal brain growth beginning in the first
few months that precedes the clinical behavioral onset of autism. The degree,
rate, and/or duration of the overgrowth may be related to neuroanatomical
and clinical outcome. The HC overgrowth in infants later diagnosed with AD
holds potential for clinical application because it is early, rapid, substantial,
common across patients, and may eventually prove to be distinctive from other
forms of head and brain enlargement, and also because its detection is simple,
inexpensive, noninvasive, objective, and reliable. The existence of such a
pronounced biological early warning signal, if confirmed by future studies,
offers hope that the causes will be equally pronounced leading to very early
diagnosis and effective biological intervention or even prevention of autism.
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