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CLINICAL REPORT
Identification and Evaluation of
Children With Autism Spectrum
Disorders
Chris Plauche´ Johnson, MD, MEd, Scott M. Myers, MD, and the Council on Children With Disabilities
ABSTRACT
Autism spectrum disorders are not rare; many primary care pediatricians care for
several children with autism spectrum disorders. Pediatricians play an important
role in early recognition of autism spectrum disorders, because they usually are the
first point of contact for parents. Parents are now much more aware of the early
signs of autism spectrum disorders because of frequent coverage in the media; if
their child demonstrates any of the published signs, they will most likely raise their
concerns to their child’s pediatrician. It is important that pediatricians be able to
recognize the signs and symptoms of autism spectrum disorders and have a
strategy for assessing them systematically. Pediatricians also must be aware of local
resources that can assist in making a definitive diagnosis of, and in managing,
autism spectrum disorders. The pediatrician must be familiar with developmental,
educational, and community resources as well as medical subspecialty clinics. This
clinical report is 1 of 2 documents that replace the original American Academy of
Pediatrics policy statement and technical report published in 2001. This report
addresses background information, including definition, history, epidemiology,
diagnostic criteria, early signs, neuropathologic aspects, and etiologic possibilities
in autism spectrum disorders. In addition, this report provides an algorithm to help
the pediatrician develop a strategy for early identification of children with autism
spectrum disorders. The accompanying clinical report addresses the management
of children with autism spectrum disorders and follows this report on page 1162
[available at www.pediatrics.org/cgi/content/full/120/5/1162]. Both clinical re-
ports are complemented by the toolkit titled “Autism: Caring for Children With
Autism Spectrum Disorders: A Resource Toolkit for Clinicians,” which contains screening
and surveillance tools, practical forms, tables, and parent handouts to assist the
pediatrician in the identification, evaluation, and management of autism spectrum
disorders in children.
INTRODUCTION
Public and physician awareness of autism has increased markedly in the new
millennium because of increased media coverage and a rapidly expanding body of
knowledge published in professional journals. Professionals who specialize in
autism have proliferated over the past 2 decades and have introduced the termi-
nology “autism spectrum disorders” (ASDs) to reflect the broader spectrum of
clinical characteristics that now define autism.
1,2
ASDs represent 3 of the pervasive
developmental disorders defined in the Diagnostic and Statistical Manual of Mental
www.pediatrics.org/cgi/doi/10.1542/
peds.2007-2361
doi:10.1542/peds.2007-2361
All clinical reports from the American
Academy of Pediatrics automatically expire
5 years after publication unless reaffirmed,
revised, or retired at or before that time.
The guidance in this report does not
indicate an exclusive course of treatment
or serve as a standard of medical care.
Variations, taking into account individual
circumstances, may be appropriate.
Key Words
autism, autism spectrum disorders,
Asperger syndrome, pervasive
developmental disorders, fragile X
syndrome, joint attention, self-injurious
behaviors, theory of mind,
neuropathologic abnormalities
Abbreviations
ASD—autism spectrum disorder
AD—autistic disorder
DSM—Diagnostic and Statistical Manual of
Mental Disorders
AS—Asperger syndrome
PDD-NOS—pervasive developmental
disorder–not otherwise specified
PCP—primary care pediatrician
AAP—American Academy of Pediatrics
IDEA—Individuals With Disabilities
Education Act
MR—mental retardation
GDD— global developmental delay
ADHD—attention-deficit/hyperactivity
disorder
FISH—fluorescence in situ hybridization
MMR—measles-mumps-rubella
JA—joint attention
ToM—theory of mind
SLP—speech-language pathologist
CHAT—Checklist for Autism in Toddlers
M-CHAT, Modified Checklist for Autism in
Toddlers
CAST—Childhood Asperger Syndrome
Test
EEG— electroencephalography
PEDIATRICS (ISSN Numbers: Print, 0031-4005;
Online, 1098-4275). Copyright © 2007 by the
American Academy of Pediatrics
PEDIATRICS Volume 120, Number 5, November 2007 1183
Guidance for the Clinician in Rendering
Pediatric Care
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Disorders, Fourth Edition (DSM-IV),
3
and the newer Diag-
nostic and Statistical Manual of Mental Disorders, Fourth
Edition, Text Revision (DSM-IV-TR)
4
: autistic disorder
(AD), Asperger syndrome (AS [this terminology will be
used in this report, although “Asperger’s disorder” is
used in the aforementioned publications]), and perva-
sive developmental disorder–not otherwise specified
(PDD-NOS). In addition to being a spectrum disorder,
autism has wide variability with respect to the presence
and intensity of symptoms, even within the DSM-IV-TR
categories, which indicates that there may be additional
subtypes.
ASDs are not rare; many primary care pediatricians
(PCPs) care for several children with ASDs. In fact, a
survey completed in 2004 revealed that 44% of PCPs
reported that they care for at least 10 children with
ASDs; however, only 8% stated that they routinely
screened for ASDs.
5
Another survey indicated that al-
though PCPs were aware of the current DSM-IV-TR
diagnostic criteria, they sometimes held beliefs about
ASDs that were outdated.
6
It is critical that PCPs recog-
nize the early signs of ASDs and be aware of new data
that support better outcomes in children whose condi-
tions are diagnosed early and who participate in appro-
priate intervention programs.
7–11
Because it is a chronic
condition, the PCP also needs to feel comfortable with
the ongoing care of children with ASDs within the con-
text of the medical home. To support PCPs in the iden-
tification and care of children with ASD, the American
Academy of Pediatrics (AAP) has developed and distrib-
uted several documents:
● The “Autism A.L.A.R.M.”
12
: a flyer that highlights the
prevalence of autism, the importance of screening and
listening to parents’ concerns, and the urgency of
making simultaneous referrals to specialists in ASDs
and early intervention programs to promote improved
outcomes.
● “Is Your One-Year-Old Communicating With You?”
13
:a
brochure that focuses on early identification of social
communication deficits and behavior problems that
may be associated with developmental disorders, pri-
marily ASDs. This brochure is intended for distribu-
tion to all parents of infants at the 9- or 12-month
well-child visit. It encourages parents to share any
concerns they have about their infant’s language de-
velopment and social skills with the pediatrician as
early as possible.
● “Understanding Autism Spectrum Disorders”
14
: a 48-page
introductory booklet for parents of children in whom
an ASD has been diagnosed recently or is suspected
strongly.
In addition, the AAP has developed an ASD toolkit
and resource guide to assist the PCP with implementa-
tion of the principles discussed herein.
Although ASDs are neurodevelopmental conditions
with strong genetic underpinnings, their exact etiology is
unknown. In 1943, Leo Kanner, a psychiatrist at Johns
Hopkins University, first described autism in a small
group of children who demonstrated extreme aloofness
and total indifference to other people.
15
In 1944, Hans
Asperger, an Austrian pediatrician who was unaware of
Kanner’s work, published an article
16
that described chil-
dren who demonstrated symptoms similar to those of
Kanner’s patients, with the exception that verbal and
cognitive skills were higher. The term “infantile autism”
first appeared as a diagnostic label in the Diagnostic and
Statistical Manual of Mental Disorders, Third Edition (DSM-
III).
17
Since then, terminology has changed and diagnos-
tic criteria have broadened.
18
Diagnostic criteria for AS
were not included in the DSM until the fourth edition
(DSM-IV). The most recent criteria for AD and AS (As-
perger’s disorder) are found in the DSM-IV-TR
4
(Tables 1
and 2, respectively). PDD-NOS, the remaining ASD, is
described in the DSM-IV-TR as a subthreshold diagnostic
term used when a child demonstrates severe and perva-
sive impairments in reciprocal social skills associated
with deficits in language skills or with the presence of
stereotypic behaviors or restricted interests or activities
but does not meet full criteria for AD or AS. Although
Rett syndrome and childhood disintegrative disorder are
included in the DSM-IV-TR listings, they are not consid-
ered ASDs but should be considered in the differential
diagnosis of each child, depending on the presenting
signs and symptoms.
EPIDEMIOLOGY
Authors of studies published early in the new millen-
nium concluded that the best estimate of current prev-
alence of ASDs in Europe and North America is approx-
imately 6 per 1000.
19–27
In 2000, the Centers for Disease
Control and Prevention organized the Autism and De-
velopmental Disabilities Monitoring Network, a multi-
site, records-based surveillance program, to study the
prevalence of ASDs. The network uses systematic
screening of developmental evaluation records for autis-
tic behaviors rather than depending on a medical or
educational diagnostic label of an ASD. In 2007, the
network reported ASD rates for 8-year-old children
ranging from 1 in 303 to 1 in 94 for 2 time periods (2000
and 2002) in a total of 14 sites in the United States; the
average rate was 1 in 150 or 6.6 per 1000 8-year-
olds.
28–31
Although these studies reflect a 10-fold increase
from studies published a half-century ago that chiefly
targeted AD alone, most of the newer studies also in-
cluded individuals with AS and PDD-NOS. One of the
few studies that analyzed the prevalence in regard to
type of ASD revealed that in Canada, where the overall
rate was 6.5 per 1000, the individual rates were 2.2
per 1000 for AD, 1.0 per 1000 for AS, and 3.3 per 1000
for PDD-NOS.
27
Studies have varied in design, and
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case-ascertainment strategies make comparisons diffi-
cult.
20–22,24,31–34
With recent heightened public awareness, parents are
more likely to raise a concern specifically about au-
tism.
35–37
In addition, as screening tools and more reliable
evaluation instruments have been developed, profes-
sionals have become increasingly proficient in recogniz-
ing and diagnosing ASD. Apart from greater awareness
and better ascertainment, additional reasons for the ap-
parent increase have been debated hotly in the lay me-
dia; in fact, the publicized “autism epidemic” may be one
of the most challenging public health issues today.
The prevalence of autism and, more recently, ASDs is
closely linked to a history of changing criteria and diag-
nostic categories. Autism first appeared as a separate
entity with specific criteria in the DSM-III in 1980.
17
In
1987, the Diagnostic and Statistical Manual of Mental Disor-
ders, Third Edition, Revised (DSM-III-R)
38
listed broadened
AD criteria and the new subthreshold category of PDD-
NOS, both of which promoted inclusion of milder cases.
Later, these changes received criticism for being too
inclusive and for promoting overdiagnosis.
39
The DSM-
IV
3
criteria published in 1994 reflected the result of years
of analyses to reduce the overinclusiveness of the DSM-
III-R criteria; however, it included AS for the first time,
which, in effect, broadened the range of disorders. Stud-
ies have revealed that the DSM-IV criteria have better
specificity (0.87) than DSM-III-R criteria.
40
The DSM-IV-
TABLE 1 Diagnostic Criteria for 299.00: AD
A. A total of six (or more) items from (1), (2), and (3), with at least two from (1), and one each from (2) and (3):
(1) qualitative impairment in social interaction, as manifested by at least two of the following:
(a) marked impairment in the use of multiple nonverbal behaviors such as eye-to-eye gaze, facial expression, body postures, and gestures to regulate social
interaction
(b) failure to develop peer relationships appropriate to developmental level
(c) a lack of spontaneous seeking to share enjoyment, interests, or achievements with other people (eg, by a lack of showing, bringing, or pointing out objects of
interest)
(d) lack of social or emotional reciprocity
(2) qualitative impairments in communication as manifested by at least one of the following:
(a) delay in, or total lack of, the development of spoken language (not accompanied by an attempt to compensate through alternative modes of
communication such as gesture or mime)
(b) in individuals with adequate speech, marked impairment in the ability to initiate or sustain a conversation with others
(c) stereotyped and repetitive use of language or idiosyncratic language
(d) lack of varied, spontaneous make-believe play or social imitative play appropriate to developmental level
(3) restricted repetitive and stereotyped patterns of behavior, interests, and activities, as manifested by at least one of the following:
(a) encompassing preoccupation with one or more stereotyped and restricted patterns of interest that is abnormal either in intensity or focus
(b) apparently inflexible adherence to specific, nonfunctional routines or rituals
(c) stereotyped and repetitive motor mannerisms (eg, hand or finger flapping or twisting, or complex whole-body movements)
(d) persistent preoccupation with parts of objects
B. Delays or abnormal functioning in at least one of the following areas, with onset before 3 years old: (1) social interaction, (2) language as used in social
communication, or (3) symbolic or imaginative play.
C. The disturbance is not better accounted for by Rett’s Disorder or childhood disintegrative disorder.
Reprinted with permission from American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR). Washington, DC: American
Psychiatric Publishing; 2000:75.
TABLE 2 Diagnostic Criteria for 299.80: Asperger’s Disorder (Referred to as AS in This Report)
A. Qualitative impairment in social interaction, as manifested by at least two of the following:
(1) marked impairment in the use of multiple nonverbal behaviors such as eye-to-eye gaze, facial expression, body postures, and gestures to regulate social
interaction
(2) failure to develop peer relationships appropriate to developmental level
(3) a lack of spontaneous seeking to share enjoyment, interests, or achievements with other people (eg, by a lack of showing, bringing, or pointing out objects of
interest to other people)
(4) lack of social or emotional reciprocity
B. Restricted repetitive and stereotyped patterns of behavior, interests, and activities, as manifested by at least 1 of the following:
(1) encompassing preoccupation with one or more stereotyped and restricted patterns of interest that is abnormal either in intensity or focus
(2) apparently inflexible adherence to specific, nonfunctional routines or rituals
(3) stereotyped and repetitive motor mannerisms (eg, hand or finger flapping or twisting, or complex whole-body movements)
(4) persistent preoccupation with parts of objects
C. The disturbance causes clinically significant impairment in social, occupational, or other important areas of functioning.
D. There is no clinically significant general delay in language (eg, single words used by 2 years old, communicative phrases used by 3 years old).
E. There is no clinically significant delay in cognitive development or in the development of age-appropriate self-help skills, adaptive behavior (other than in social
interaction), and curiosity about the environment in childhood.
F. Criteria are not met for another specific Pervasive Developmental Disorder or Schizophrenia.
Reprinted with permission from American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR). Washington, DC: American
Psychiatric Publishing; 2000:75.
PEDIATRICS Volume 120, Number 5, November 2007 1185
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TR
4
criteria for AD and AS are unchanged; however, the
text description of PDD-NOS was edited slightly to in-
crease specificity. Collaboration with European groups
that worked on the revised International Statistical Classi-
fication of Diseases and Related Health Problems (10th edi-
tion)
41
promoted better conformity between the 2 clas-
sification systems.
AD did not become a diagnosis for which children
became eligible to receive special education services un-
til passage of the Individuals With Disabilities Education
Act (IDEA) in 1990.
42
Before the IDEA was enacted,
children were labeled as having conditions such as men-
tal retardation (MR), learning disability, speech impair-
ment, or emotional disturbance to obtain eligibility for
services.
43
Hence, after passage of the IDEA, the resulting
increase in the number of children served under the AD
category reflected both newly diagnosed young children
entering the school system and older children who were
previously eligible for special services under a different
educational label. This reflects the phenomenon of “di-
agnostic substitution,” whereby the number of children
receiving special education under other categories (pri-
marily MR, speech impairment, and learning disabilities)
has decreased over the same time period. In addition,
some increase in prevalence may be attributable to in-
accuracies in diagnosis for a number of reasons, includ-
ing labeling biases when schools used less rigorous cri-
teria than those needed for a DSM diagnosis,
44–48
when
educational funding trends influenced diagnosis,
49
and/or when parents of children with marginal criteria
advocated for the AD label to qualify for supplementary
services (eg, year-round schooling) described in the
IDEA amendments.
50,51
The impact of these factors on
current prevalence estimates has been controversial and
illustrates the reason why educational administrative
data reported in some studies that receive media atten-
tion should not be considered for epidemiologic stud-
ies.
47,48,52–56
Just at the time when school eligibility laws were
changing, the Americans With Disabilities Act of 1990
57
was passed, obliging states to administer their programs
in the most integrated settings appropriate to the needs
of the person with disabilities. This was the culmination
of a long series of state and federal legislation that pro-
moted closure of institutions and encouraged govern-
ments to support families in their efforts to raise their
children with disabilities at home. Thus, children with
autism, especially those with comorbid MR and behavior
problems who might have been institutionalized in the
past, began to attend community schools and to be
“counted” in educational prevalence data.
Other factors that may also be contributing to the
perceived increase in prevalence include the recent iden-
tification of children with genetic disorders unrelated to
ASDs who also sometimes can meet criteria for an ASD,
such as Down syndrome
58,59
and CHARGE (coloboma,
heart disease, choanal atresia, retarded growth and de-
velopment and/or central nervous system anomalies,
genital anomalies and/or hypogonadism, and ear anom-
alies and/or deafness) syndrome.
60
Finally, diagnosis of
an ASD may be made in an older family member with
milder symptoms that were previously unrecognized
until after the diagnosis of a younger child.
61
Regardless of the study, the year conducted, or the
reported rate of prevalence, more boys than girls are
consistently found to be affected with ASDs, with male-
to-female ratios ranging from 2:1 to 6.5:1.
24,28,29,34,62
The
male-to-female ratio is even higher for high-functioning
autism and AS, ranging from 6:1 to as high as 15:1.
63
(In
recognition of these statistics and for the sake of brevity,
this report uses masculine pronouns.)
ETIOLOGY
ASDs are biologically based neurodevelopmental disor-
ders that are highly heritable.
64
Despite this fact, the
exact cause still is unknown. Finding the cause has been
daunting because of genetic complexity and phenotypic
variation. ASDs are complex heritable disorders that in-
volve multiple genes and demonstrate great phenotypic
variation. Estimates of recurrence risks, based on family
studies of idiopathic ASDs, are approximately 5% to 6%
(range: 2%–8%) when there is an older sibling with an
ASD and even higher when there are already 2 children
with ASDs in the family.
65–68
In a minority of cases (⬍10%), ASDs may be associ-
ated with a medical condition or a known syndrome.
20,21
Although ASDs are believed to be mainly genetic in
origin, environmental factors may modulate phenotypic
expression.
64,69
Advanced paternal age
70,71
and maternal
age
71,72
have been shown to be associated with an in-
creased risk of having offspring with ASDs, possibly be-
cause of de novo spontaneous mutations and/or alter-
ations in genetic imprinting. Environmental exposures
may act as central nervous system teratogens in early
gestational life.
73
Some researchers have suggested that
an epigenetic mechanism (heritable changes in gene
expression that occur without changes in DNA se-
quence) may be responsible.
74
Thus, it has become more
and more apparent that the etiology is multifactorial
with a variety of genetic and, to a lesser extent, envi-
ronmental factors playing a role.
75
Two major strategies have been used in the search for
the ASD genes: targeted cytogenetic/molecular studies
and whole-genome screens of families of children with
ASD.
76–79
The first strategy depends on developing a hy-
pothesis regarding the pathogenesis of ASDs, focusing on
a potential candidate gene and testing it genetically for
an association with ASDs. Candidate genes in ASDs in-
clude, among others, those that seem to play a role in
brain development (eg, cerebellar Purkinje cell prolifer-
ation) or neurotransmitter function (eg, serotonin).
80
The second strategy uses an indirect method and does
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not require investigators to make assumptions regarding
the mechanism of inheritance. Instead, families with
multiple members who demonstrate an ASD (multiplex
families) are studied to identify recurring DNA markers
(break points, translocations, duplications, and dele-
tions) present in affected members but not in unaffected
members. Unfortunately, progress in determining a ge-
netic etiology using this method has been impaired,
because the phenotypic end points of ASDs are not well
defined. Changing DSM criteria and inconsistent ascer-
tainment strategies, which results in a hazy delineation
between affected versus unaffected family members, ob-
scure outcomes and challenge interpretation of results.
67
This phenotypic heterogeneity has challenged molecular
searches for the ASD gene(s) despite several genome-
wide screens of the International Molecular Genetic
Study of Autism Consortium and multicenter collabora-
tive efforts over the past couple of decades.
78,81–84
Al-
though at least 1 autism-linked abnormality has been
found on almost every chromosome, sites on a few
chromosomes (X, 2, 3, 7, 15, 17, and 22) seem to be
more promising than others.
67,68,75,79,85–90
Maternally de-
rived 15q duplications are common; depending on the
investigator, yields vary from 1% to 10%,
91
with most in
the range of 1% to 3%.
92,93
Patients with these duplica-
tions may not display dysmorphic features, but they
often have hypotonia and/or global developmental delay
(GDD) and may develop seizures later. The abnormality
can often be identified on high-resolution karyotype
analysis. Other less common abnormalities have also
been reported.
94
Finally, the male predominance noted above also sug-
gests a genetic role in the inheritance of autism. Several
genetic processes can lead to male predominance, in-
cluding causative genes located on the X chromosome
(X-linked disorders) and imprinted genes, but the reason
for male predominance in autism is not completely un-
derstood.
95
In a discussion of etiology, subtyping ASDs as either
idiopathic or secondary is helpful.
67,79,95
For the purposes
of this discussion, the term “idiopathic” ASDs refers to
cases in which children meet criteria for ASDs but do not
have a comorbid associated medical condition known to
cause ASDs. Most individuals with an ASD have the
idiopathic type. Children with idiopathic ASDs demon-
strate variable behavioral phenotypes, are somewhat less
likely to have comorbid GDD/MR, and generally do not
have dysmorphic features that herald a recognizable
syndrome. Nevertheless, twin and family studies have
revealed that idiopathic ASDs are heritable and have a
recurrence rate of 5% to 6%.
67,94,95
The term “secondary”
ASDs refers to cases with an identifiable syndrome or
medical disorder known to be associated with ASDs.
Whereas earlier reviews reported that the proportion of
individuals with ASDs who have a comorbid syndrome
or medical condition was 10% to 20%,
2,96–98
the propor-
tion has decreased to less than 10% when using more
recent data sets.
79,89,95,99–101
In a meta-analysis of 23 epi-
demiologic studies, Chakrabarti and Fombonne
20,21
re-
vealed that a recognizable condition was identified in
only 6% of those with a confirmed ASD. The rate of
coexisting MR (cognitive impairment associated with an
IQ of ⬍70) in children with ASDs seemed to decrease
from 90% before the 1990s to less than 50% after
2000,
28,29,34,35,102,103
possibly because of improved methods
in testing intelligence in this population and to the in-
creased awareness of children with ASD with milder
features and higher functioning. This trend is important,
because coexisting severe MR, especially in the presence
of dysmorphic features, increases the likelihood of iden-
tifying a known disorder.
89,104–108
Neurogenetic syn-
dromes that seem to play a causative role or otherwise
are associated with ASDs include, but are not limited to:
● Fragile X syndrome
109,110
: Fragile X syndrome is the
most common known genetic cause of AD and of MR
in males. The phenotype includes MR, macrocephaly,
large pinnae, large testicles (particularly after pu-
berty), hypotonia, and joint hyperextensibility. Iden-
tifying a patient with fragile X syndrome is important
for genetic counseling purposes, because the diagnosis
has implications for other family members. Depending
on the prevalence of comorbid MR in study subjects
with ASD, the etiologic yield of fragile X syndrome–
DNA testing has ranged from 0% to 8%, with a me-
dian of approximately 3% to 4%.
99,109,111
On the other
hand, as many as 30% to 50% of individuals with
genetically confirmed fragile X syndrome will demon-
strate some characteristics of ASDs.
102,110
● Neurocutaneous disorders: Tuberous sclerosis
112–116
is
characterized by hypopigmented macules (sometimes
requiring a Wood’s lamp examination for visualization
in young children), fibroangiomata, kidney lesions,
central nervous system hamartomas, seizures, MR,
and autistic and/or attention-deficit/hyperactivity dis-
order (ADHD)–like behaviors. Although tuberous
sclerosis is a dominant disorder (with genes located at
9q and 16p), most cases represent new mutations.
Although it is the most common neurocutaneous dis-
order, neurofibromatosis is less likely to be associated
with ASDs. It also is autosomal-dominant, with half of
cases representing new mutations of the neurofibro-
matosis 1 gene on 17q.
117
It is characterized by cafe´au
lait macules and freckling in the axillary and inguinal
regions, neurofibromas, and ocular Lisch nodules. Al-
though most patients have a benign course and nor-
mal intelligence, a small subset of individuals have MR
and behavioral features that are consistent with ASDs.
● Phenylketonuria
118
: phenylketonuria now is a rare
cause of ASDs and MR in the United States, because it
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is preventable as a result of newborn screening and
dietary intervention.
● Fetal alcohol syndrome
119
: Children who are exposed
to alcohol during gestation have an increased risk of
ASDs in addition to other neurodevelopmental disor-
ders.
● Angelman syndrome
93,94,120–123
: Angelman syndrome is
associated with loss of the maternally expressed ubiq-
uitin-protein ligase gene (UBE3A) on 15q through
deletion, paternal uniparental disomy, or imprinting
errors. Children with Angelman syndrome present
with GDD (and often are nonverbal), hypotonia in
early childhood, wide-based ataxic gait, seizures, and
progressive spasticity. Angelman syndrome associated
with a deletion of 15q can be detected with fluores-
cence in situ hybridization (FISH) testing; however,
when it results from uniparental disomy, methylation
studies are necessary.
● Rett syndrome
124–127
: Rett syndrome usually presents
with a classic phenotype and should be considered in
all females who demonstrate autistic-like regression,
especially if they have microcephaly, seizures, and
hand-wringing stereotypies. Retrospective videos
have revealed early subtle motor symptoms during the
first year of life.
128
Now that it is possible to confirm
this diagnosis with DNA testing (methyl CpG-binding
protein 2 [MECP2]) in approximately 80% of cases, it
has become apparent that there is a spectrum of se-
verity, and some patients may present with atypical
features including those consistent with ASDs. Rett
syndrome is much less common in males, and the
presentation is more varied. Some males die in infancy
as a result of neonatal encephalopathy; others with
comorbid Klinefelter syndrome (as well as a few males
[in isolated case reports] with a normal number of sex
chromosomes) demonstrate more classic symp-
toms.
129,130
● Smith-Lemli-Opitz syndrome
131
: Smith-Lemli-Opitz
syndrome is a rare (1 in 20 000) autosomal-recessive
disorder caused by a metabolic error in cholesterol
biosynthesis. Although most patients present with
multiple congenital anomalies, failure to thrive, and
MR, some may present with subtle physical features
such as webbing (syndactyly) of the second and third
toes, mild hypotonia, and autistic features. Recurrence
risk is 25%; thus, appropriate genetic counseling is
important.
Whether the aforementioned conditions play a direct
or indirect etiologic role or simply are associated with
ASDs, they still represent a small minority of patients
with ASDs. Conversely, a few children with genetic syn-
dromes that are characterized by features quite different
from ASDs also may meet DSM-IV-TR criteria. For ex-
ample, recent studies have reported that 6% to 7% of
children with Down syndrome (typically characterized
by relatively good social skills compared with those in
other domains)
59
and almost 50% of children with
CHARGE syndrome (associated with mutations of the
CHD7 gene
132
) meet criteria for one of the ASDs.
60
There
have also been a few isolated reports of a mitochondrial
and/or metabolic abnormality (eg, carnitine deficiency)
being associated with an ASD, but the significance of
these reports is not clear.
133
Increased and decreased levels of T lymphocytes, im-
munoglobulins, and antibrain autoantibodies in the sys-
temic circulation have been reported.
134
These have been
observed chiefly in retrospective case studies of patients
with idiopathic ASDs, but systematic prospective studies
have confirmed neither their existence nor their rele-
vance.
87
Prospective studies have revealed that, except
for a few individuals with recurrent infections, healthy
children with ASDs generally have normal immune
function.
135
Some studies have reported increased rates
of autoimmune disorders in families of children with
ASDs,
136
particularly in the mothers (eg, thyroid disor-
ders
137
and psoriasis
138
); however, the relevance of these
common disorders to ASDs in children is unknown.
Furthermore, studies have shown no increase in auto-
immune disorders of the central nervous system, and
patients with ASDs did not themselves exhibit autoim-
mune disorders.
139
The contribution of possible immu-
nologic dysfunction remains to be further defined.
Environmental Issues
Regardless of the mechanism, a review of studies pub-
lished in the past 50 years revealed convincing evidence
that most cases of ASDs result from interacting genetic
factors.
67,95
However, the expression of the autism
gene(s) may be influenced by environmental fac-
tors.
66,67,69,140
Although currently under investigation,
these factors may represent a “second-hit” phenomenon
that primarily occurs during fetal brain development.
That is, environmental factors may modulate already
existing genetic factors responsible for the manifestation
of ASDs in individual children.
Prenatal Period
Because many of the developmental brain abnormalities
known to be associated with ASDs occur during the first
and second trimesters of pregnancy,
141,142
environmental
factors (eg, teratogens, such as thalidomide and valproic
acid)
73
are more likely to play a role in the fetus via
maternal factors. It is possible that maternal illness (eg,
rubella) during pregnancy plays a role.
143,144
Recently,
the possible association between fetal testosterone con-
centration and certain autistic behaviors such as abnor-
mal social relationships and restricted interests at 4 years
of age was investigated.
145
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Perinatal Period
The effects of birth weight, duration of gestation, and
events around the time of birth have been investigated
also, but findings have not been consistent.
72,146–152
A
significant association between term newborn encepha-
lopathy and children later diagnosed with ASD was re-
ported recently.
72,150
Badawi et al
150
reported that 5% of
survivors of newborn encephalopathy were diagnosed
with an ASD, which represented an almost sixfold in-
crease compared with matched controls. This increase
may represent a genetically derived predisposition
(which makes the infants vulnerable to both encepha-
lopathy and ASD) or an independent mechanism.
Postnatal Period
Etiologic possibilities occurring after birth have been
proposed—in particular, measles-mumps-rubella (MMR)
vaccine
153
and mercury-containing vaccines.
154–156
In 2001, the Institute of Medicine
157
reviewed epidemi-
ologic population-based studies and concluded that
there was no evidence of a causal association between
the MMR vaccine and autism. Studies that examined the
association between MMR vaccine and autism since the
publication of that review have supported this conclu-
sion.
27,95,103,158–161
Questions also have been raised about
the effects of environmental mercury exposure (includ-
ing mercury-containing vaccines) on brain development
in ASDs and other developmental disabilities.
154–156
Mer-
cury, in its organic form, is a known neurotoxin with
neurologic sequelae, including motor impairment and
visual and intellectual deficits, depending on the age at
exposure and the type of mercury. There is no evidence
to date that children with neurodevelopmental disabili-
ties, including autism, in the United States have in-
creased mercury concentrations or environmental expo-
sures.
162
Using large data sets from the United States,
Sweden, and Denmark, to date, no consistent associa-
tion has been found between thimerosal-containing vac-
cines and neurodevelopmental outcomes or prevalence
of ASDs.
27,95,162–164
Despite evidence to the contrary, a
recent survey of parents of children with ASDs revealed
that 54% believed that their child’s ASD was caused by
immunizations; 53% thought it was caused by genet-
ics.
165
Although the previous discussion reveals the wide
variety of conditions known to be associated with ASDs,
currently, an etiologic investigation of the individual
child with an ASD infrequently identifies a known cause
in the absence of GDD/MR, dysmorphic features, a pos-
itive family history, and/or a focal neurologic examina-
tion.
2,20,21,89,101,106–108
NEUROPATHOLOGY AND NEUROIMAGING
In recent years, intense research efforts have focused on
elucidating the neurobiological basis of ASDs. A growing
body of evidence from neuropathology and neuroimag-
ing studies indicates that there are fundamental differ-
ences in brain growth and organization in people with
ASDs that have their origin in the prenatal period but
extend through early childhood and into adulthood.
Neuropathologic studies of brain tissue from people
with autism have revealed several abnormalities
166–171
including:
● reduced numbers of Purkinje cells in the cerebellum;
● abnormal maturation of the forebrain limbic system,
including reduced neuronal size, increased cell-pack-
ing density, and decreased complexity of the neuropil
(ie, the complex net of axonal, dendritic, and glial
branching in which the nerve cell is embedded);
● abnormalities in frontal and temporal lobe cortical
minicolumns, which are more numerous, smaller, and
less compact in their cellular configuration and dem-
onstrate reduced neuropil space in the periphery
167
;
● developmental changes in cell size and number in the
nucleus of the diagonal band of Broca, deep cerebellar
nuclei, and inferior olive; and
● brainstem abnormalities and neocortical malforma-
tions (eg, heterotopias).
171
The most consistent neuropathologic findings suggest
pathology that arises in utero. The association of in-
creased risk of ASDs associated with prenatal exposure
to teratogens, such as thalidomide and valproic acid,
suggests that early insults during critical periods of brain
development (as early as 20 –24 days after conception in
the case of thalidomide) may be sufficient to cause
ASDs.
171
However, all of these neuropathologic findings
are based on detailed study of a relatively small number
of brains, and further investigation is required. Limited
availability of brain tissue from people with well-char-
acterized ASDs and age-matched controls has impeded
neuropathologic investigations. Efforts to remedy this
are underway with the establishment of the Autism
Tissue Project (1-800-272-4622 [for physicians] or
1-877-333-0999 [for families]; www.memoriesofhope.
org).
168
Kanner, in his initial clinical description of autism,
noted large head size in several of his patients.
15
In-
creased head circumference has since been shown to be
a common physical finding in children with ASDs, and
20% to 30% have macrocephaly, defined as a head
circumference that measures more than 2 SDs above the
mean.
172,173
MRI studies have supported the finding of
increased brain volume in children with ASDs, with
90% of toddlers with ASDs having larger-than-normal
brain volumes in 1 study.
174,175
Postmortem brain
weights also are increased.
166
Children later diagnosed
with an ASD have been shown, as a group, to have
average or below-average head circumference at birth,
with acceleration in brain growth during the first year of
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life, leading to above-average head circumference or
overt macrocephaly.
176,177
Fewer adults with ASDs have
been found to exhibit increased brain size compared
with controls, indicating that there may be deceleration
of brain growth at some point beyond early child-
hood.
176,178,179
It is interesting to note that increased blood
concentrations of brain-derived neurotrophic factor and
several other neurotrophins have been detected in new-
born infants who are later diagnosed with ASDs.
180
This
finding, if replicated, may have implications regarding
the mechanism of early brain overgrowth. Age-related
differences in serotonin synthesis capacity also have
been demonstrated between children with ASDs and
children in control groups,
181
which leads to speculation
regarding the neurotrophic role of serotonin in abnor-
mal brain growth and organization in children with
ASDs.
In addition to whole-brain volume differences, spe-
cific regional gray- and white-matter volumetric differ-
ences have been described. The frontal, limbic, basal
ganglia, and cerebellar regions have been implicated
most consistently.
172,182–184
Abnormalities in sulcal and
gyral anatomy have been found by using surface-map-
ping techniques.
185,186
The regional gray- and white-mat-
ter volume differences also seem to be age related, al-
though larger cross-sectional studies and longitudinal
studies are needed to clarify the meaning of these find-
ings.
A variety of functional MRI studies during cognitive
tasks or in response to visual or auditory stimuli suggest
that individuals with ASDs use different cognitive strat-
egies and, in some cases, different brain areas to process
certain types of information.
182,187
For example, func-
tional neuroimaging techniques have indicated the pres-
ence of abnormalities in face recognition and executive
functioning in adults with high-functioning ASDs.
188
Hy-
poactivation of the fusiform gyrus in face-recognition
tasks has been one of the most consistent findings
187
and,
in concert with abnormalities in amygdala activation,
may relate to the abnormalities in gaze fixation that are
seen in people with ASDs.
189
Functional MRI evidence
has also been used to postulate impaired “connectivity”
between various cortical regions in the brains of people
with ASDs.
190–192
Most recently, some investigators have
attempted to explain deficits in empathy, imitation, and
language as abnormalities in the functioning of mirror
neuron systems.
193
These systems are a newly discovered
subset of cells found in several areas of the brain that
seem to fire when an individual simply observes anoth-
er’s actions—that is, it seems they directly reflect actions
performed by another in the observer’s brain. They also
may play a role in the ability to recognize and empathize
with or “mirror” the feelings of others. These functional
brain differences provide intriguing links between the
neuroanatomical substrate and the characteristic clinical
features of people with ASDs.
Although neuroimaging research has identified volu-
metric and other abnormalities in groups of patients with
ASDs compared with controls, a reliable marker has not
been identified, and routine clinical neuroimaging for
individuals with ASDs is not recommended.
106,107,183,194
CLINICAL SIGNS
Whereas severe social skills deficits and restricted, repet-
itive, and stereotyped patterns of behavior, interests, and
activities are core features of all ASDs, significant lan-
guage delays are characteristic of only AD and PDD-
NOS.
3,4
One of the most challenging aspects in recogniz-
ing ASDs is the wide heterogeneity of features in
individual children. There is no pathognomonic feature;
however, a few of the early social deficits (eg, delayed or
absent joint attention [JA]) seem to be fairly reliable red
flags for ASDs. The autism spectrum encompasses an
extremely heterogeneous phenotype with indistinct end
points, especially at the mild end of the spectrum. The
severity of each of the core deficits varies significantly
among children with ASDs.
Although the social deficits occur earlier and may be
more specific, they can be subtle and less often recog-
nized or articulated by parents. Speech delays usually
prompt parents to raise concerns to their child’s PCP.
Most parents become concerned between 15 and 18
months of age but may delay discussing their concerns
with their child’s physician for several months.
35,195–198
Recently, the media and public agencies have raised
public awareness about the importance of recognizing
the early signs, including those present during the first
years of life. This being the case, it is anticipated that
parents may begin to voice concerns to their infant’s
pediatrician earlier and that these concerns may now
target the often earlier-appearing social deficits. Presen-
tations can differ widely from one child to the next;
some are perceived by parents as “different” during the
first few months of life, others present with delayed
speech development during the second year of life, and
still others may appear to be normal only to regress and
lose skills after the first year of life.
199,200
AS in children
may go unnoticed until they are of school age, when
teachers notice difficulties with peer interactions. Ex-
panded reviews regarding early signs are available.
201–203
Social Skills Deficits
Although more specific than language deficits, social
deficits appearing in the first 2 years of life often have
escaped parent recognition.
204–206
Children with ASDs
universally demonstrate deficits in social relatedness de-
fined as the inherent drive to connect with others and
share complementary feeling states.
207
Children with
ASDs often do not appear to seek connectedness; they
are content being alone, ignore their parents’ bids for
attention, and seldom make eye contact or bid for oth-
ers’ attention with gestures or vocalizations. In later
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years, they have difficulty sharing the emotional state of
others in cooperative games and group settings and may
have few, if any, friends.
Deficits in JA seem to be one of the most distinguish-
ing characteristics of very young children with
ASDs.
198,208–216
JA is a normal, spontaneously occurring
behavior whereby the infant shows enjoyment in shar-
ing an object (or event) with another person by looking
back and forth between the two. Later, gestures and/or
speech also can be used to engage another’s attention
with regard to the objects and events simply for the
enjoyment of sharing the experiences. Just like other
developmental skills, development of JA skills is step-
wise; it occurs in stages beginning in the first few months
of life. Similar to language skills, receptive JA skills usu-
ally are mastered before expressive ones. JA begins with
joyous smiling in recognition of and response to a parent
or familiar caregiver’s smiles and vocalizations. At ap-
proximately 8 months of age, an infant will follow the
parent’s gaze and look in the same direction when a
parent looks away (ie, to check the time). Children begin
to “follow a point” at approximately 10 to 12 months of
age. If a parent points in the direction of an interesting
object or event and says, “Look!” the typically develop-
ing child will look in the intended direction and then,
after seeing the object/event, look back at the parent in
acknowledgment and shared expression. Infants with
ASD may not follow a point, even when one tries re-
peatedly in a loud voice calling their name or uses phys-
ical prompts, such as touching the child’s shoulder be-
fore pointing.
204
They may look in the indicated direction
eventually, but this is not followed by shared looking
and expression.
At approximately 12 to 14 months of age, the typi-
cally developing child will begin himself to initiate a
point, at first to request a desired object that is out of
reach and, a couple of months later, to draw the parent’s
attention to share an interesting object, person, or event.
Depending on his speech skills, he may utter simple
sounds (“uh”) or actual words while pointing. Pointing
to request an object is called “protoimperative pointing.”
Deficits vary, as some children with ASDs may make
rudimentary pointing efforts by opening and closing
their hand while it is raised in the direction of the desired
item but without any back-and-forth looking between it
and the caregiver. Another frequent strategy is to take
the parent’s hand to lead him or her to the object. At 14
to 16 months of age, the typically developing child will
begin to point simply to “comment” about or “share” an
interesting object/event (which is called “protodeclara-
tive pointing”). As he points, he will look alternatively
between the object/event of interest and the parent. It is
the shared social experience, not the tangible object/
event, that the child seeks. Children with ASDs consis-
tently fail to point to “comment” at age-appropriate
times, and when they do, they are less likely to show
positive affect and connectedness during the act. Some
high-functioning children with ASDs may point to label
objects, shapes, and colors that they have learned in a
rote fashion, but this often is done without any intent of
communicating in a social context and is not considered
JA. Mastery of JA seems to be necessary for functional
language development; in fact, mastery of protodeclara-
tive pointing seems to be a reliable predictor of func-
tional language development within 1 year.
7,217–219
JA
skills progress to involve ongoing back-and-forth bids for
attention and social interactions with multiple emo-
tional expressions, sounds, words, and other gestures.
Orienting to social stimuli—in particular, turning
consistently to respond to one’s own name—is an early
skill (8–10 months of age) that often is deficient in
children with ASDs.
215,220
However, it is not specific to
children with ASDs, because children with hearing im-
pairments also may fail to orient to their name. In fact,
parents of children later diagnosed with ASDs often raise
a concern about hearing. Hearing seems “selective” in
that children with ASDs may hear and attend well to
environmental sounds but not to human voices.
221
Social
referencing
222
is the ability to recognize the emotional
states of others as they respond to various stimuli. When
faced with a novel situation, a typically developing in-
fant might look to his mother for an indication of de-
light, anger, or fear in her facial expression. His facial
expression then usually will mimic hers, although he
may not fully understand the situation. A child with an
ASD engages in less imitation.
223
Because children with ASDs lack fundamental social
skill building blocks, they may be less likely to develop
appropriate peer relationships according to age and lan-
guage ability. They may have few or no friends, and when
they do, the relationships may evolve around the child’s
own special interests. Another factor that impedes lasting
friendships is impaired central coherence or the inability to
interpret stimuli in a global way.
224,225
Instead, they focus
on the parts, make less use of context, and miss the “big
picture,” which makes social interactions challenging. They
also have difficulties understanding the perspective of oth-
ers or lack “theory-of-mind” (ToM) skills. ToM is the
awareness that others have thoughts and emotions that are
independent from one’s own; it is the ability that allows
one to infer states of mind on the basis of external behav-
ior.
226,227
Typically developing children begin to have some
sense of mental states of others by 4 years of age.
197,228,229
Because of ToM impairments, children with ASDs have
difficulties with empathy, sharing, and comforting. Baron-
Cohen
230
coined the term “mindblindedness” when refer-
ring to persons with ASDs who demonstrate severe ToM
deficits.
Communication Deficits
Most children who are later diagnosed with AD and
PPD-NOS present to their PCP with “speech delay,” al-
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though this may change as parents are becoming more
aware of social milestones. As noted previously, most
parents sense something is wrong by the time the child
is 18 months old.
195–198
Lack of speech has been consid-
ered a hallmark of AD, especially when it is associated
with the lack of desire to communicate and lack of
nonverbal compensatory efforts such as gestures. How-
ever, children with milder symptoms, especially those
with normal cognitive skills, may have some speech.
Their speech may not be functional or fluent and may
lack communicative intent. It can be scripted (from fa-
vorite videos or television programs) and stereotypic.
Echolalia, sometimes called “parroting,” is the repetition
of another person’s speech. Echolalia is classified as “im-
mediate” when the child repeats vocalizations promptly
after hearing them or “delayed” when there is a time
lapse (hours, days, weeks). Typically developing children
pass through a “vocabulary-burst stage,” when brief pe-
riods of immediate echolalia are not unusual.
197
On the
other hand, echolalia in children with ASDs may persist
throughout the life span and consist of a mixture of
immediate and delayed varieties. Utterances of children
with ASDs may be more clearly articulated, have a more
monotone quality, and/or consist of larger verbal
“chunks” (ie, entire television advertisement jingles,
video reenactments, or recitations of nursery rhymes)
than those of typically developing children. Sometimes,
echolalia may even give the impression of “advanced”
speech because of sophisticated vocabulary, grammar,
and syntax. The clinician should be careful to differen-
tiate between typical and autistic echolalia; usually, a
formal evaluation by a speech-language pathologist
(SLP) is needed. Such an assessment also may reveal a
dissociation between these “advanced” expressive skills
and delayed receptive ones in that the child may be
unable to follow simple 1-step commands, which is a 12-
to 14-month-old skill. Some parents will note that their
child seems overly “independent” because, rather than
ask for desired objects, he uses advanced motor skills to
obtain them himself (ie, moving a stool to a counter top
to obtain an object at an age younger than typically
expected). Some children with ASDs become quite
skilled at rotely labeling colors, shapes, numbers, and
letters of the alphabet, yet they are unable to point to
them when asked to do so by another or incorporate the
labels into functional language. A few may later develop
hyperlexia or advanced verbal reading without corre-
sponding comprehension skills.
Some children with ASDs say “pop-up words” with-
out any apparent stimulus or communicative intent.
They are spontaneous and inconsistent, although some-
times they may occur during acutely stressful situations.
These words are said out of context for a short period of
time (days or weeks) and then, as suddenly as they
might pop up for no apparent reason, they disap-
pear.
197,119
Children with ASDs also may develop “lan-
guage” in overlearned or gestalt phrases that are ac-
quired and spoken almost as a single “giant-word” (ie,
Whatisit? Idontknow). At the same time, they are un-
able to combine words in novel or original phrases or
sentences that convey true meaning.
Although lack of speech, scripted speech, parroting
without communicative intent, and pop-up and giant
words are common classic presentations, earlier pre-
speech deficits often exist that, if detected, could facili-
tate earlier diagnosis.* These deficits include:
● lack of appropriate gaze;
● lack of warm, joyful expressions with gaze;
● lack of the alternating to-and-fro pattern of vocaliza-
tions between infant and parent that usually occurs at
approximately 6 months of age (ie, infants with ASDs
usually continue vocalizing without regard for the
parent’s speech);
● lack of recognition of mother’s (or father’s or consis-
tent caregiver’s) voice;
● disregard for vocalizations (ie, lack of response to
name), yet keen awareness for environmental sounds;
● delayed onset of babbling past 9 months of age;
● decreased or absent use of prespeech gestures (wav-
ing, pointing, showing);
● lack of expressions such as “oh oh” or “huh”;
● lack of interest or response of any kind to neutral
statements (eg, “Oh no, it’s raining again!”)
The AAP brochure “Is Your One-Year-Old Communicat-
ing With You?”
13
was developed to help raise parent and
physician awareness of these earlier social communica-
tion milestones and to promote recognition of symptoms
of ASDs before 18 months of age.
Regression
Approximately 25% to 30% of children with ASDs begin
to say words but then stop speaking, often between the
ages of 15 and 24 months.
199,200,208
Regression of skills in
children with ASDs may also include loss of gestural
communication (wave, point, etc) and social skills (eg,
eye contact and response to praise) or a combination of
both. Regression can be gradual or sudden, and it may be
superimposed on subtle preexisting developmental de-
lays or atypical development, such as an unusually in-
tense interest in objects or other nonsocial stimuli during
the first year of life.
205
Although it may be tempting to
attribute regression to environmental stressors (eg, birth
of a new sibling or a move to a new house), this results
in a delay in diagnosis. Regression is a well-documented
hallmark of ASDs and should always alert the PCP to
consider ASDs.
*Refs 197, 204, 213, 214, 219, and 222.
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Asperger Syndrome
Children with AS may have mild or limited speech de-
lays (see the DSM-IV-TR
4
criteria in Table 2) and escape
recognition until preschool or early school age, when
their inability to make friends becomes a concern. Al-
though often unnoticed, language development usually
is atypical. Children with AS often are quite verbal about
a certain topic of interest, but they are unable to express
simple feelings or recognize the feelings and viewpoints
of others. Speech may be fluent but limited to only a few
topics, typically those that hold a strong, all-consuming
interest for the child. Speech also can be overly formal
(pedantic), which is a reason why children with AS
sometimes are described as “little professors.”
227
Children
with AS also have deficits in the social use of language
(pragmatics): how to choose a topic of conversation;
understanding and producing appropriate tempo, facial
expression, and body language during conversation;
turn taking; recognizing when the partner has lost in-
terest in a topic; knowing when to start, sustain, and end
a conversation on the basis of listener cues; knowing
when and how to repair a communication breakdown;
and using the appropriate degree of formality and po-
liteness.
197,227
Children with AS especially have difficulty
sustaining a conversation on a topic that is initiated by
another. Language may seem odd, self-centered, and not
listener responsive and results in a monotone mono-
logue. They may demonstrate unique delivery of speech
(prosody) in regard to intonation, volume, rhythm,
pitch, and personal space that also tends to disregard
listener needs. Children with AS may have difficulty
with abstract reasoning and discussion of thoughts and
opinions of others. Inability to discern and judge the
conversational intents of others, especially when their
conversation includes words or phrases with ambiguous
meanings, impairs their ability to understand metaphors,
humor, teasing idioms, irony, lies, jokes, and faux
pas.
226,227,229
Older children with high-functioning AD or
PDD-NOS and fluent speech also may demonstrate some
of the above-mentioned language characteristics.
Play Skills
Lack of, or significantly delayed, pretend play skills cou-
pled with persistent sensory-motor and/or ritualistic
play are characteristic of ASDs. Some children with se-
vere ASDs may never progress past the sensory-motor
play stage. They mouth, twirl, bang, and manipulate
objects in a stereotypic or ritualistic manner. The play of
children with ASDs often is repetitive and lacks creativ-
ity and imitation.
3,4
Typical examples include spinning
the wheels or lining up cars instead of “driving” them,
arranging crayons instead of coloring with them, or
stacking blocks in the same sequence time after time.
Often they prefer to play with common objects (string,
sticks, rocks, or ballpoint pens) rather than store-bought
toys with the exception of trains or characters from
favorite videos and television shows. Puzzles, especially
shape-matching ones and computerized “puzzle games,”
also are quite popular.
222
Children with ASDs often are
content to play alone for hours, requiring little attention
or supervision. Often this “play” is either constructive
(puzzles, computer games, and blocks), ritualistic (lining
objects up or sorting/matching shapes or colors) or sen-
sory-motor (mouthing, banging, twirling) in nature.
Children with ASDs may seem to enjoy chase games and
roughhousing, but it is often the sensory-motor aspects
of these activities, rather than their social aspects, that
are enjoyable. They have trouble interacting in groups
and cooperating in the social rules of more sophisticated
games. Often they are left out, ignored, and at high risk
of being victimized and bullied by peers.
231
Restricted, Repetitive, and Stereotyped Patterns of Behavior,
Interests, and Activities
Children with ASDs can demonstrate atypical behaviors
in a variety of areas including peculiar mannerisms,
unusual attachments to objects, obsessions, compul-
sions, self-injurious behaviors, and stereotypies. Stereo-
typies are repetitive, nonfunctional, atypical behaviors
such as hand flapping, finger movements, rocking, or
twirling.
3,4,203
Although most stereotypies are harmless,
they are problematic in that they may prevent the child
from accomplishing a task or learning new skills. Al-
though stereotypies are distinctive and obvious, they are
not specific to children with ASDs, because many chil-
dren with profound MR and/or severe sensory deficits
also demonstrate stereotypies. Even typically developing
toddlers, especially before the onset of fluent language,
may flap their arms briefly when they are excited or
frustrated. Stereotypies associated with ASDs often do
not appear until after 3 years of age
232
and commonly
manifest as finger flicking, unusual eye gazing, habitual
toe walking, and/or persistent sniffing and licking of
nonfood items.
Although most children, at some time during their
early development, form attachments with a stuffed an-
imal, special pillow, or blanket, children with ASDs may
prefer hard items (ballpoint pens, flashlight, keys, action
figures, etc). Moreover, the attachment is more persis-
tent, in that they may insist on holding the object at all
times, although these are rarely, if at all, used in real
“play.” Whereas younger children with ASDs may have
restricted interests in regards to objects, the restricted
interests in those with AS more often relate to topics and
facts.
227
For example, rather than carrying a toy train at
all times, there is an obsession with train schedules.
Sometimes the item/topic of interest may be typical for
any child, but it is the degree of interest that is abnormal.
For example, similar to typically developing children, a
child with an ASD may be fascinated with dinosaurs, but
he knows far more details about them and persists in
playing or discussing them to the exclusion of all else.
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Perseveration, or continuation of speech or play to an
exceptional degree or beyond a desired point, is common
in children with ASDs. Children with ASDs may protest
vigorously when forced to transition from an activity or
topic of interest or when a usual routine is changed.
Without warning, these protests may quickly escalate to
severe and prolonged temper tantrums characterized by
aggression or self-injurious behaviors.
Self-injurious behaviors (head banging, skin picking,
eye poking, hand biting) are stereotypies that may cause
bodily harm and are more common in children with
severe GDD/MR (intellectual disabilities) or ASDs with
comorbid GDD/MR.
233
Self-injurious behaviors may be
precipitated by frustration during unsuccessful commu-
nication attempts, transitions, anxiety in new environ-
ments, boredom, depression, fatigue, sleep deprivation,
or pain. The presence of self-injurious behaviors, aggres-
sion, and other extreme behaviors may prevent the child
from participating in integrated activities in the commu-
nity with typically developing peers and cause significant
family stress.
Additional Coexisting Conditions That Are Not Core Features
in the DSM-IV-TR
Cognitive Abnormalities (GDD/MR or Intellectual Disability,
Learning Differences, and Splinter/Savant Skills)
The prevalence of comorbid GDD/MR or intellectual
disability (the appropriate term depends on age and
availability of both a standardized IQ score and a formal
assessment of adaptive skills) with ASDs was estimated
to be approximately 90% before 1990.
62
On the basis of
later studies published in the 1990s, consensus guide-
lines reported the prevalence as approximately 70% to
75%.
1,2,106,107,234
Prevalence studies published in the new
millennium have reported rates of ASDs with comorbid
GDD/MR of just under 50%,
28,29,34,103
whereas 2 English
studies reported rates as low as 26% to 29%.
20,21
Better
ascertainment of children without cognitive deficits (in
particular AS, which by definition is characterized by
normal intelligence), improved professional training,
and more effective strategies/tools for evaluating cogni-
tive abilities in children with ASDs all may contribute to
the decreasing prevalence of comorbid GDD/MR.
One unique characteristic of ASDs is the “uneven-
ness” of skills. Abilities may be significantly delayed in
some areas of development yet “advanced” in others,
often because of exceptional focusing, memory, calcula-
tion, music, or art abilities.
235
They may be labeled as
“splinter skills” when they serve no purpose in day-to-
day life and do not improve functional outcomes. Rarely,
highly developed talents or savant skills may promote a
vocation that provides financial independence and, oc-
casionally, national recognition.
236–238
Sensory-Motor Symptoms
Although sensory symptoms (eg, hyperacusis) are more
frequent and prominent in children with ASDs, there is
no evidence that sensory symptoms differentiate chil-
dren with ASDs from children with other developmental
disabilities.
239
Children with ASDs may demonstrate si-
multaneous hyposensitivities and hypersensitivities for
stimuli within the same sensory modality.
240
For exam-
ple, they may seem overly sensitive to certain environ-
mental noises but lack response to human voice, or they
may visually inspect the details of an object but not
notice the comings and goings of other people in the
room. Others may have oral aversions and/or total-body
“tactile defensiveness” to soft touch (fabric bumps on
socks and sweatshirts) or hugs yet be insensitive to
pain.
241
Sensory factors related to food, such as texture,
color, and taste, may lead to highly restricted diets. More
research is needed to operationalize the concept of sen-
sory integration and possible interventions and define its
role in ASDs.
In addition to unusual motor stereotypies that serve
as defining characteristics of ASDs discussed previously,
some children with ASDs also may demonstrate atypical
motor development, poor coordination, or deficits in
praxis (motor planning, execution, and sequencing).
240
Some investigators believe that, although not a defining
characteristic by DSM standards, motor clumsiness is a
distinguishing characteristic of AS.
86,242
Finally, some
children may appear to be “hyperactive” and motor
driven with an exterior focus of attention and actually
meet criteria for comorbid ADHD (although current
DSM-IV-TR criteria exclude making the diagnosis of
ADHD in the presence of an ASD).
8,240,243
Other children
may be hypoactive and withdrawn and have an interior
focus of attention.
240
In summary, ASDs are characterized by a broad array
of clinical features; some are more specific to ASDs than
others (JA deficits versus stereotypies). Familiarity with
the early social and preverbal communication deficits
will help the PCP recognize ASDs earlier, which should,
in turn, facilitate the prompt initiation of appropriate
interventions.
SURVEILLANCE AND SCREENING
Because the prevalence of ASDs is approximately 6 to 7
per 1000 in the United States,
28,29
PCPs are likely to
provide care for children with ASDs. Early identification
of ASDs is important, because it allows early interven-
tion, etiologic investigation, and counseling regarding
recurrence risk. The medical home is an important set-
ting for surveillance and screening to detect ASDs and
other developmental disorders. In the past, it was not
unusual for parents’ initial concerns to be dismissed and
for diagnosis and intervention to be delayed.
195,196,244,245
In a recent study in metropolitan Atlanta, Georgia, the
mean age of the first evaluation for 115 8-year-old chil-
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dren with ASDs was 48 months, and the mean age of the
first ASD diagnosis was 61 months.
35
The goal of this clinical report is to help pediatricians
identify children at an earlier age who are at risk of an
ASD. An ASD-specific surveillance and screening algo-
rithm (Fig 1) has been developed to facilitate the iden-
tification process. It builds on the developmental surveil-
lance and screening algorithm for pediatric preventive
care visits that was published in the 2006 policy state-
ment “Identifying Infants and Young Children With De-
velopmental Disorders in the Medical Home: An Algo-
rithm for Developmental Surveillance and Screening.”
246
General Developmental Surveillance and Screening
According to the AAP policy statement “Identifying In-
fants and Young Children With Developmental Disor-
ders in the Medical Home: An Algorithm for Develop-
mental Surveillance and Screening,”
246
“surveillance” is
the ongoing process of identifying children who may be
at risk of developmental delays, and “screening” is the
use of standardized tools at specific intervals to support
and refine the risk. As an analogy, whereas surveillance
represents a “moving picture” of the child’s unfolding
development, screening represents “snapshots” of the
child’s development at specific times. Developmental
surveillance should occur at every preventive visit
throughout childhood and includes the following com-
ponents: eliciting and attending to the parents’ concerns;
maintaining a developmental history; making accurate
and informed observations of the child; identifying the
presence of risk and protective factors; and documenting
the process and findings.
246
Research has revealed that
parents have valid concerns about their children’s devel-
opment, although careful interpretation of the concerns
is needed.
247,248
However, parental concerns may not be
shared if the PCP does not ask about the child’s devel-
opment, and lack of parental concern about develop-
ment does not imply typical development.
247–250
There-
fore, a systematic surveillance strategy must be used for
all children.
246
Screening with a standardized develop-
mental tool should be performed whenever concerns are
raised through the ongoing surveillance process. The
AAP also recommends that all children be screened with
a standardized developmental tool at specific intervals
(ie, at the 9-, 18-, and 24- or 30-month visits) regardless
of whether a concern has been raised or a risk has been
identified during the surveillance process (see the AAP
developmental screening and surveillance algorithm
246
).
Surveillance for ASD
Surveillance at the first preventive care visit (Fig 1, Steps
1a and 2) should begin with a family history to deter-
mine if there are any family members, especially a sib-
ling, who have been diagnosed with ASDs. Because the
risk of having symptoms of ASDs in younger siblings of
children with ASDs is approximately 10 times higher,
the pediatrician needs to be extra vigilant in monitoring
for early abnormal signs. Studies of infant siblings with
ASDs have revealed that very subtle early signs do exist
and can be perceived during the first year of life.
204,205
Until recently, most knowledge regarding very early
signs was obtained from retrospective systematic reviews
of home videos, particularly first birthday party vid-
eos.
251
Studies of home videos at earlier ages have pro-
vided additional retrospective information that reveals
subtle abnormalities in infants who were thought to be
typically developing and later diagnosed as having re-
gressive autism.
205
Several groups of investigators are
following younger siblings of children diagnosed with
ASDs and providing prospective information as symp-
toms emerge in these infants at high risk.
204
Preliminary
results support the feasibility of recognizing subtle signs
of ASDs in infants at high risk.
204,206,213,214,252,253
Some of
the very early signs reported by several investigators
include extremes of temperament and behavior (ranging
from marked irritability to alarming passivity); poor eye
contact; poor response to other’s voices, especially to
one’s name being called
252
; poor attempts at interactive
play; more interest in looking at objects than people;
delayed pointing to request or share; decreased to-and-
fro babbling and jargoning; and lack of warm, joyful,
reciprocating expressions.
Surveillance should include asking parents open-
ended questions about their concerns regarding the
child’s development and behavior (Step 2). Parental con-
cerns about inconsistent hearing or unusual responsive-
ness also are important; for example, parents may notice
that the child responds consistently to a quiet sound,
such as the crinkle of a plastic snack bag, but not to a
human voice calling his name. In addition, parent con-
cerns may be stimulated by comments made by other
care providers such as child care staff or preschool teach-
ers. Recently, however, the public media have signifi-
cantly increased awareness of ASDs and sometimes has
stimulated unnecessary concerns. The AAP patient edu-
cation brochure “Is Your One-Year-Old Communicating
With You?”
13
can be distributed to all parents at their
child’s 9- or 12-month preventive visit to educate them
about early social communication milestones to help
them identify valid areas of concern.
Surveillance also includes asking age-specific ques-
tions about whether certain developmental milestones
have been attained. When this approach is used, it is
important to include social and emotional milestones in
addition to the traditional motor, language, and prob-
lem-solving milestones
254,255
(see www.firstsigns.org). To
recognize ASDs as early as possible, it is important to ask
about the development of verbal and nonverbal com-
munication, reciprocal social interaction (including eye
contact, JA and social referencing, and sharing of inter-
ests or achievements), and representational or pretend
play skills. The American Academy of Neurology and
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8:
1. Provide Parental Education
2. Simultaneously Refer for:
a. Comprehensive ASD Evaluation
b. Early Intervention/Early Childhood
Education Services
c. Audiologic Evaluation
3. Schedule Follow-up Visit
4. Re-enter Algorithm at 1b
Surveillance and Screening Algorithm: Autism Spectrum Disorders (ASDs)
1a - Developmental concerns,
including those about social skill
deficits, should be included as one
of several health topics addressed at
each pediatric preventive care visit
through the first 5 years of life.
(Go to step 2)
1b – At the parents’ request, or when a concern is
identified in a previous visit, a child may be scheduled
for a “problem-targeted” clinic visit because of concerns
about ASD. Parent concerns may be based on
observed behaviors, social or language deficits, issues
raised by other caregivers, or heightened anxiety
produced by ASD coverage in the media. (Go to step 2)
2 - Developmental surveillance is a flexible, longitudinal, continuous, and cumulative process whereby health care
professionals identify children who may have developmental problems. There are 5 components of
developmental surveillance: eliciting and attending to the parents’ concerns about their child’s development,
documenting and maintaining a developmental history, making accurate observations of the child, identifying the
risk and protective factors, and maintaining an accurate record and documenting the process and findings. The
concerns of parents, other caregivers, and pediatricians all should be included in determining whether
surveillance suggests that the child may be at risk of an ASD. In addition, younger siblings of children with an
ASD should also be considered at risk, because they are 10 times more likely to develop symptoms of an ASD
than children without a sibling with an ASD. Scoring risk factors will help determine the next steps. (Go to step 3)
For more information on developmental surveillance, see “Identifying Infants and Young Children With Developmental Disorders in the Medical Home: An Algorithm for
Developmental Surveillance and Screening” (
Pediatrics 2006;118:405-420).
3 - Scoring risk factors:
•
If the child does not have a sibling with an ASD and there are no concerns
from the parents, other caregivers, or pediatrician: Score=0 (Go to step 4)
•
If the child has only 1 risk factor, either a sibling with ASD or the concern of
a parent, caregiver, or pediatrician: Score=1 (Go to step 3a)
•
If the child has 2 or more risk factors: Score=2+ (Go to step 8)
3a:
Is the Patient at
Least 18-Months
Old?
3a –
•
If the child’s age is <18
months, Go to step 5a
•
If the child’s age is ≥18
months, Go to step 5b
4 – In the absence of established risk factors and parental/provider concerns (score=0), a level-1 ASD-specific tool should be
administered at the 18- and 24-month visits. (Go to step 5c) If this is not an 18- or 24-month visit, (Go to step 7b).
Note: In the AAP policy, “Identifying Infants and Young Children With Developmental Disorders in the Medical Home: An Algorithm for Developmental
Surveillance and Screening”, a general developmental screen is recommended at the 9-, 18-, and 24-or 30-month visits and an ASD screening is
recommended at the 18-month visit. This clinical report also recommends an ASD screening at the 24-month visit to identify children who may regress after
18 months of age.
5a - If the child’s age is <18
months, the pediatrician should
use a tool that specifically
addresses the clinical
characteristics of ASDs, such
as those that target social-
communication skills.
(Go to step 6a)
5b - If the child’s
age is ≥18 months,
the pediatrician
should use an
ASD-specific
screening tool.
(Go to step 6a)
5c – For all children
ages 18 or 24 months
(regardless of risk
factors), the pediatrician
should use an ASD-
specific screening tool.
(Go to step 6b)
AAP-recommended strategies for using ASD screening tools: “Autism: Caring for Children with Autism Spectrum Disorders: A Resource Toolkit for Clinicians” (in press)*
6a – When the result of the screening is
negative
,
Go to step 7a
When the result of the screening is
positive
,
Go to step 8
6b – When the result of the ASD screening (at 18-
and 24-month visits) is
negative, Go to step 7b
When the result of the ASD screening (at 18- and 24-
month visits) is
positive
,
Go to step 8
7a – If the child demonstrates risk but has a negative screening result,
information about ASDs should be provided to parents. The
pediatrician should schedule an extra visit within 1 month to address
any residual ASD concerns or additional developmental/ behavioral
concerns after a negative screening result. The child will then re-enter
the algorithm at 1b. A “wait-and-see” approach is discouraged. If the only risk factor is a sibling with
an ASD, the pediatrician should maintain a higher index of suspicion and address ASD symptoms at
each preventive care visit, but an early follow-up within 1 month is not necessary unless a parental
concern subsequently arises.
7b – If this is not an
18- or 24-month
visit, or when the
result of the ASD
screening is
negative, the pediatrician can inform the
parents and schedule the next routine
preventive visit. The child will then re-enter the
algorithm at 1a.
8 –
If the screening result is positive for possible ASD in step 6a or 6b, the pediatrician should provide peer reviewed
and/or consensus-developed ASD materials. Because a positive screening result does not determine a diagnosis of
ASD, the child should be referred for a comprehensive ASD evaluation, to early intervention/early childhood education
services (depending on child’s age), and an audiologic evaluation. A categorical diagnosis is not needed to access
intervention services. These programs often provide evaluations and other services even before a medical evaluation
is complete. A referral to intervention services or school also is indicated when other developmental/behavioral
concerns exist, even though the ASD screening result is negative. The child should be scheduled for a follow-up visit
and will then re-enter the algorithm at 1b. All communication between the referral sources and the pediatrician should
be coordinated.
AAP information for parents about ASDs includes: “Is Your One-Year-Old Communicating with You?*” and “Understanding Autism Spectrum Disorders.*”
*Available at www.aap.org
7a:
1. Provide Parental Education
2. Schedule Extra Visit Within 1
Month
3. Re-enter Algorithm at 1b
2:
Perform Surveillance
Score 1 for Each Risk Factor:
- Sibling with ASD
- Parental Concern
- Other Caregiver Concern
- Pediatrician Concern
3:
What is the
Score?
4:
Is this an 18- or
24-Month Visit?
5a:
Evaluate Social-
Communication
Skills
5b:
Administer ASD-
Specific Screening
Tool
5c:
Administer ASD-
Specific Screening
Tool
6a:
Are the Results
Positive or
Concerning?
6b:
Are the Results
Pos itive or
Concerning?
7b:
1. Schedule Next
Preventive Visit
2. Re-enter Algorithm at 1a
1a:
Pediatric Patient at
Preventive Care
Visit
1b:
Extra Visit for Autism-
Related Concern,
ASD Risk Factor, or
Other Developmental/
Behavioral Concern
FIGURE 1
Continued
PEDIATRICS Volume 120, Number 5, November 2007 1197
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Child Neurology Society practice parameter on screening
and diagnosis of autism
107
suggests that the following “red
flags” are absolute indications for immediate evaluation:
● no babbling or pointing or other gesture by 12
months;
● no single words by 16 months;
● no 2-word spontaneous (not echolalic) phrases by 24
months; and
● loss of language or social skills at any age.
Pediatricians should become concerned (Step 2)ifthe
answers to these questions reveal deficits or delays in
milestones or if behaviors typical of ASD are observed
during an office visit.
In older, more developmentally advanced children,
including many with AS, surveillance questions (Step 2)
may elicit concerns about social interaction difficulties
related to more subtle communication problems, such as
pragmatic language impairment and lack of understand-
ing of nonliteral forms of communication (figures of
speech, humor, sarcasm, metaphor, etc), difficulty tak-
ing the perspective of another (resulting in inappropriate
or offensive behavior, gullibility, and lack of common
sense), and obsession with facts, details, or collections.
Pragmatic language refers to the use of language in social
interaction and includes instinctive rules governing fac-
tors, such as topic maintenance and turn taking in con-
versation, how sentences are made to fit in with the flow
of a conversation, how unspoken premises are inferred,
how degrees of formality and politeness are signaled,
and prosody (modulation of the intonation, rhythm,
volume, timing, and stress of the voice). The parents
may note that the child lacks true friendships and is
viewed as odd, eccentric, or “weird” by his ⬘peers.
In addition, during the well-child visit, the PCP may
try to interact with the patient by using a few simple
strategies depending on the child’s age. For example, the
PCP can note the response when calling the child’s name
at the 12-month well-child visit, and/or the JA mile-
stone of “following a point” can be elicited at the 12-,
18-, and 24-month well-child visits as part of routine
developmental surveillance. In the latter, the pediatri-
cian points to an object at a distance, such as a picture on
the wall or a mobile, while making a verbal request for
the child to look. Whereas a typically developing child
would look in the direction of the point and then after-
ward engage in eye contact with the physician or the
parent, a child with an ASD may appear to be oblivious
to the PCP’s gesture and verbal request. This is true even
if the PCP increases the intensity of the stimulus by
calling louder, adding the child’s name, or touching the
child’s shoulder first and then pointing and exclaiming,
“Look!” The child may still fail to respond even if the
parent repeats the maneuvers. With an older, higher-
functioning child, the PCP may enter into conversation
with the child to determine if he has difficulty interpret-
ing a figure of speech, telling a joke, or explaining why
a joke is funny. In addition, the PCP may ask a question
or two about one of the child’s areas of interest to
observe a response that is characteristic of AS, such as a
long-winded, overly precise, or pedantic reply. Any of
these responses should raise the concern of a PCP.
Each concern raised by a parent, other caregiver, or
the pediatrician constitutes a separate risk factor, as does
a positive family history of a sibling with an ASD (Step 2).
To determine how to proceed, the pediatrician should
assess the number of risk factors (Step 3). Possible scores
include 0, 1, 2, 3, or 4.
1. If no concerns have been raised during the course of
the preventive visit and the child is not the sibling of
a child who has already been diagnosed with an ASD,
then the PCP should proceed to Step 4. ASD-specific
screening is indicated only if the visit is the 18- or
24-month preventive visit. See Step 5c below.
2. If the child’s only risk factor is having a sibling with
an ASD, then the PCP should make sure the parents
are aware of early signs of ASDs and continue to
monitor carefully.
253
If the parents call with a concern
between scheduled routine preventive visits, the
child should be seen within 1 or 2 weeks and reenter
the algorithm at Step 1b for a “targeted visit” to ad-
dress concerns about ASDs. If the score ⫽ 1 as a result
of a single concern (parent, other caregiver, or PCP),
the PCP should screen the child formally with a stan-
dardized tool; the choice of tool will depend on the
child’s age (Step 3a) (see “Screening Tools for Imple-
mentation of Step 5”).
3. If 2 or more risk factors are identified, then the PCP
should proceed directly to Step 8, which includes sev-
eral activities that should be accomplished simulta-
neously and without delay.
Screening for ASDs (Steps 5a–5c)
Physician estimates of the developmental status of chil-
dren are much less accurate when only clinical impres-
sions, rather than formal screening tools, are used,
256,257
yet a minority of PCPs use formal developmental screen-
ing instruments,
258,259
and few pediatricians specifically
screen for ASDs.
5
A standardized screening tool should
be administered at any point when concerns about ASDs
are raised spontaneously by a parent or as a result of
clinician observations or surveillance questions about
social, communicative, and play behaviors (Steps 5a and
5b).
246,260
In the general developmental screening and
surveillance policy statement discussed previously, the
AAP also recommended administering a standardized
autism-specific screening tool on all children at the 18-
month preventive care visit (Step 5c).
246
The AAP Autism
Expert Panel responded to the statement with a com-
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mentary
260
that suggested a repeat screening be per-
formed at 24 months of age (Step 5c) to identify those
who may regress after 18 months of age.
Screening Tools for Implementation of Step 5
A variety of general developmental screening tools are
available to practitioners.
246
General developmental
screening tools are appropriate for use with unselected
primary care populations and are likely to detect ASDs in
many young children because of associated language
and cognitive delays, but they do not differentiate chil-
dren with ASDs from those with other developmental
disorders, and data are not available on sensitivity for
detection of ASDs. Tools to screen specifically for ASDs
also have been designed (Table 3), but they have not yet
been validated on children younger than 18 months.
The PCP should remember that screening tools are likely
to be overinclusive, so children with developmental and
behavioral disorders other than ASDs also might have
positive screening results. Similar to other developmen-
tal screening measures, ASD-specific screening tools
may rely entirely on parent report, or they may require
direct observation and engagement by the clinician. Par-
ent-report tools often have the advantage of being brief,
inexpensive, and practical in the office setting. The peo-
ple who know the child best are surveyed and can de-
scribe the child’s behavior over time in a variety of
settings rather than being constrained to sampling be-
havior in one setting at one point in time.
Step 5a: Tools for Use in “at-Risk” Children Younger Than
18 Months
Although several tools are in development for screening
children younger than 18 months, none are available yet
for routine clinical use. The Infant/Toddler Checklist
from the Communication and Symbolic Behavior Scales
Developmental Profile
261
(which can be downloaded at
www.brookespublishing.com/store/books/wetherby-cs-
bsdp/CSBSDP㛭Checklist.pdf) may be particularly well
suited for identifying 6- to 24-month-old children who
are at risk of ASDs, because it focuses on social and
communication skills. It is anticipated that this and other
screening tools under investigation as possible ASD-spe-
cific tools for use in infants younger than 18 months may
prove valuable in identifying children at high risk and will
become available to clinicians in the near future.
213,262,263
Step 5b: Tools for at-Risk Children 18 Months and Older
ASD-specific screening tools are available for children 18
months and older, and many of them are age specific.
Recently, such tools have been classified as “level 1” or
“level 2” screening tools.
264
Level 1 screening tools are
administered to all children within the context of a
primary care medical home and are designed to differ-
entiate children who are at risk of ASDs from the general
population, especially those with typical development.
Level 2 screening tools are used more often in early
intervention programs or developmental clinics that
serve children with a variety of developmental prob-
lems; they help to differentiate children who are at risk
of ASDs from those at risk of other developmental dis-
orders such as GDD or specific language impairment.
Level 2 screening tools generally require more time and
training to administer, score, and interpret than level 1
measures. There is considerable overlap between the
concept of a level 2 screening tool and that of a diagnos-
tic instrument.
264,265
Level 2 screening measures may be
used as part of a diagnostic evaluation, but they should
not be used in isolation to make a diagnosis.
Properties of some level 1 and 2 ASD screening tools
are reviewed in Table 3. Reported sensitivity and speci-
ficity values are included, but in most cases, sensitivity
and specificity of the instruments have been determined
only in clinical samples or in populations that included a
mixture of clinical and population-based samples, and
they must be interpreted with caution. Estimates of sen-
sitivity and specificity of developmental screening tests
may be unstable, and they are not the only criteria that
should be used to assess validity.
266
In low-prevalence
conditions, such as ASDs, the positive predictive value of
screening tools will be low even with good sensitivity
and specificity, whereas the negative predictive value
will be quite high. Many of the existing ASD-specific
screening measures are being revised or further evalu-
ated, and new tools are being developed to address some
of their weaknesses.
Some measures, such as the Checklist for Autism in
Toddlers (CHAT),
267
Modified Checklist for Autism in
Toddlers (M-CHAT),
268
and Pervasive Developmental
Disorders Screening Test-II Primary Care Screener,
269
were designed specifically for early detection of ASDs in
young children. The CHAT and M-CHAT are level 1
screening tools that are available at no cost to practitio-
ners for use in primary care (Table 3).
For older children who are diagnosed later with AS,
school personnel often raise concerns to the parents.
Staff may then administer a published AS-specific tool.
Although many level 2 screening tools have been mar-
keted for use in older children who have been identified
as being at risk of AS, further study is needed before any
one of them can be recommended as superior to oth-
ers.
270
See Table 3 for characteristics of selected AS
screening tools.
Step 5c: Tools for Screening Children Without Risk Factors
at the 18- and 24-Month Preventive Visit
Level 1 ASD tools described in Step 5b also are appropri-
ate for routine screening of young children without any
identified risk.
Among the tools designed for screening the elemen-
tary school–aged population, only the Childhood As-
perger Syndrome Test (CAST) has been assessed in a
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TABLE 3 Selected Level 1 and 2 ASD Screening Measures
Screening Tool Age Format (No. of Items) Time to
Complete, min
Reported
Sensitivity
Reported
Specificity
Selected Key
References
Availability
Level 1
a
CHAT 18–24⫹ mo Parent interview or questionnaire
and interactive (parent: 9;
clinician: 5)
5 0.18–0.38
b
;
0.65
c
0.98–1.0
b
;
1.0
c
Baron-Cohen et al,
267
Baron-Cohen et
al,
272
Baird et al,
19
Scambler et al
273
Download: www.autismresearchcentre.com/tests/chat㛭test.asp
CHAT, Denver Modifications 18–24⫹ mo Parent interview or questionnaire
and interactive (parent: 9;
clinician: 5)
5 0.85
c
1.0
c
Scambler et al
273
CHAT scoring modifications; available in Scambler et al
273
Checklist for Autism in
Toddlers-23 (CHAT-23)
16–86 mo (all
had
mental
ages of
18–24 mo)
Parent interview or questionnaire
and interactive (parent: 23,
clinician: 5)
10 0.84–0.93
c
(part A);
0.74
c
(part B)
0.77–0.85
c
(part A);
0.91
c
(part B)
Wong et al
274
Combination of M-CHAT and CHAT items; protocol available in
Wong et al
274
CAST 4–11 y Questionnaire completed by
parent (37)
10 0.88–1.0
d
0.97–0.98
d
Scott et al,
275
Williams et al,
235
Williams et al
276
Download: www.autismresearchcentre.com/tests/cast㛭test.asp
M-CHAT 16–48 mo Questionnaire completed by
parent (23)
5–10 0.85
d
0.93
d
Dumont-Matthieu
and Fein,
277
Robins et al
268
Download: www.dbpeds.org/media/mchat.pdf or
www.firstsigns.org/downloads/m-chat.pdf; for scoring:
www.firstsigns.org/downloads/m-chat㛭scoring.PDF
Pervasive Developmental
Disorders Screening Test-
II, Primary Care Screener
(PDDST-II PCS)
18–48 mo Questionnaire completed by
parent (22)
10–15 0.92
c
0.91
c
Siegel
269
Purchase: PsychCorp/Harcourt Assessment
(www.harcourtassessment.com)
Level 2
Asperger Syndrome
Diagnostic Scale (ASDS)
5–18 y Questionnaire completed by
parent, teacher, or clinician
(50)
10–15 0.85
c
Myles et al,
278
Campbell
270
Purchase: Pro-Ed (www.proedinc.com)
Autism Behavior Checklist
(ABC)
ⱖ18 mo Behavioral checklist completed
by interviewer (57 )
10–20 0.38–0.58
c
0.76–0.97
c
Krug et al
279
Purchase: Pro-Ed (www.proedinc.com) as part of the Autism
Screening Instrument for Educational Planning (ASIEP-2)
Autism Quotient
(AQ)–Adolescent Version
11–16 y Questionnaire completed by
parent (50)
15 0.89
c
1.0
c
Baron-Cohen et al
280
Download:
www.autismresearchcentre.com/tests/aq㛭adolescent㛭test.asp
Autism Spectrum Screening
Questionnaire (ASSQ)
6–17 y Questionnaire completed by
parent (27)
10 0.62–0.82
c
(parent);
0.65–
0.70
c
(teacher)
Ehlers et al
281
Questions are included as an appendix in Ehlers et al
281
Childhood Autism Rating
Scale (CARS)
⬎2 y Behavioral checklist completed
by trained interviewer/
observer (15)
Variable 0.92–0.98
c
;
0.94
c
0.85
c
Eaves and Milner,
282
Perry et al,
283
Schopler et al
284
,
Sevin et al
285
Purchase: Western Psychological Services
(www.wpspublish.com)
Gilliam Asperger’s Disorder
Scale (GADS)
3–22 y Questionnaire completed by
parent, teacher, or clinician
(32)
10 Gilliam,
286
Campbell
270
Purchase: Pro-Ed (www.proedinc.com)
Gilliam Autism Rating Scale–
2nd Edition (GARS-2)
3–22 y Questionnaire completed by
parent or teacher (42)
5–10 Gilliam
287
Purchase: Pro-Ed (www.proedinc.com)
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TABLE 3 Continued
Screening Tool Age Format (No. of Items) Time to
Complete, min
Reported
Sensitivity
Reported
Specificity
Selected Key
References
Availability
Krug Asperger’s Disorder
Index (KADI)
6–21 y Questionnaire completed by
parent or clinician (32)
15–20 0.78
c
0.94
c
Krug and Arick,
288
Campbell
270
Purchase: Pro-Ed (www.proedinc.com)
Pervasive Developmental
Disorders Screening
Test-II, Developmental
Clinic Screener (PDDST-
II, DCS)
18–48 mo Questionnaire completed by
parent (14)
10–15 0.73
c
0.49
c
Siegel
269
Purchase: PsychCorp/Harcourt Assessment
(www.harcourtassessment.com)
Pervasive Developmental
Disorders Screening
Test-II, Autism Clinic
Severity Screener
(PDDST-II, ACSC)
18–48 mo Questionnaire completed by
parent (12)
10–15 0.58
c
0.60
c
Siegel
269
Purchase: PsychCorp/Harcourt Assessment
(www.harcourtassessment.com)
Screening Tool for Autism in
Two-Year-Olds (STAT)
24–36 mo Interactive, requires specific
training (12)
20 0.92
d
0.85
d
Stone et al,
289
Stone
et al
290
Author: Wendy Stone, PhD (triad@vanderbilt.edu)
Social Communication
Questionnaire (SCQ)
(formerly the Autism
Screening Questionnaire
关ASQ兴)
ⱖ4 y Questionnaire completed by
parent (40)
5–10 0.85–0.96
c
0.67–0.80
c
Berument et al,
291
Rutter et al
292
Purchase: Western Psychological Services
(www.wpspublish.com)
The measures were selected on the basis of availability of some published psychometric properties (in English) with scoring instructions and pass/fail cutoffs or the equivalent.
a
Level 1 tools are most likely to be used in primary care settings.
b
Population-based sample.
c
Clinical sample.
d
Clinical and population-based samples.
Adapted from Coonrod EE, Stone WL. Screening for autism in young children. In: Volkmar FR, Paul R, Klin A, Cohen D, eds. Handbook of Autism and Pervasive Developmental Disorders. 3rd ed. Vol 2. Hoboken, NJ: John Wiley & Sons; 2005:707–729; Campbell JM. Diagnostic
assessment of Asperger’s disorder: a review of five third-party rating scales. J Autism Dev Disord. 2005;35:25–35; and Rutter M, Bailey A, Lord C, et al. The Social Communication Questionnaire (SCQ) Manual. Los Angeles, CA: Western Psychological Services; 2003.
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large, unselected population as a level 1 screening
tool.
271
The authors concluded that the CAST is useful as
a screening test for ASDs in epidemiologic research but
that there is not enough evidence to recommend it for
routine screening in the general population as part of a
public health program.
271
In addition, the AAP does not
currently recommend universal screening of school-
aged children with a level 1 AS-specific tool.
See Appendix 1 for reimbursement codes.
Results of Screening (Steps 6a and 6b)
If the screening result for an at-risk child is negative in
Step 6a, the PCP should proceed to Step 7a, provide
parent educational materials (such as the AAP brochure,
“Is Your One-Year-Old Communicating With You?”
13
or the
AAP parent booklet, “Understanding Autism Spectrum Dis-
orders”
14
) and schedule an extra visit (Step 1b) within 1
month to address residual concerns. If the only risk
factor is having a sibling with an ASD, an extra visit is
not necessary unless the parents become concerned after
the visit. When the screening result is negative for chil-
dren without risk at the 18- or 24-month preventive
visit (Step 6b), the PCP should proceed to Step 7b and
schedule the next routine preventive care visit (Step 1a).
If the screening result is positive (Steps 6a or 6b)or2or
more risk factors are present at Step 3, the PCP should
proceed to Step 8, at which simultaneous activities
should take place in an expedient manner. The PCP
should consider the possibility that the child with a
negative ASD screening result may have another devel-
opmental disorder that would warrant further investiga-
tion and referral to resources similar to those listed in
Step 8.
When surveillance does not identify any risk factors
and the visit is not an 18- or 24-month visit (Step 4), no
screening is recommended, and the PCP may proceed
directly to Step 7b.
Step 8: Activities Needed When Multiple Risk Factors Are
Present or When the ASD Screening Result Is Positive
Activities described herein will depend on certain com-
munity characteristics, especially in regard to obtaining a
comprehensive evaluation. Depending on the number of
ASD experts in a given community, the interval wait for
an appointment may be long. Thus, it is important that
the PCP simultaneously accomplish all of Steps 8.1
through 8.4 while the family is waiting for a specialty
appointment to confirm or rule out an ASD diagnosis.
Step 8.1: Provide Parental Education
If the PCP feels fairly certain that the child has a devel-
opmental disorder that falls somewhere in the autism
spectrum, it will be helpful to give the parents reading
materials. As discussed in the introduction to this report,
the AAP has published “Understanding Autism Spectrum
Disorders,” an educational booklet for parents with this
intent.
14
The comprehensive evaluation will progress
more efficiently if the parents are more knowledgeable
about the characteristic clinical symptoms of ASDs and
can report them more accurately. Some PCPs are reti-
cent to share their concerns with parents, fearful that
premature “labeling,” although it is tentative, might
cause undo stress and anxiety on the part of the family.
However, sincerity, honesty, and admitting uncertainty
is appreciated by most parents. On the other hand, con-
cealing a concern and taking a “wait-and-see” approach
rarely is appreciated; in fact, this strategy often breeds
parental discontent and, worse, resentment and anger.
With the recent high visibility in the media, most parents
(unlike before the 1990s) now are aware of ASDs and
may suspect it and search the Internet for information. It
is important that they receive peer-reviewed and con-
sensus-driven information that is evidence based and
that they understand how to interpret Web-site infor-
mation that is not peer reviewed.
Step 8.2.a: ASD Comprehensive Evaluation
For some children, the diagnosis might be quite obvious
to the PCP who is using the DSM-IV-TR criteria as a
guide. In others, the diagnosis may be challenging, es-
pecially when externalizing behavioral symptoms are
mild or variable and/or there are associated comorbid
disorders. Ideally, the definitive diagnosis of an ASD
should be made by a team of child specialists with ex-
pertise in ASDs. Unfortunately, teams are not available
in every locale, and when they are, long waiting lists
may exist. Most communities will have at least 1 pedi-
atric subspecialist (eg, child neurologist, developmental
pediatrician, psychiatrist) with at least some expertise in
making an ASD diagnosis. Other professionals, such as
child psychologists, SLPs, pediatric occupational thera-
pists, and social workers with expertise in ASDs, can be
helpful by performing independent evaluations, often
using standardized tools that can assist in the diagnostic
process, especially when no team or pediatric “expert” is
available. Child psychologists with appropriate training
and experience can make the diagnosis independently
and often do so, especially in school systems. Recently,
the American Speech-Language-Hearing Association
published guidelines that stated that an SLP with exper-
tise in ASDs can make the diagnosis independently
when other resources are not available.
294,295
Older chil-
dren who first present with symptoms of AS after school
entry often are first recognized and evaluated by the
school district’s educational diagnostic team and subse-
quently, but unfortunately not always, referred to a
health care professional.
If it seems fairly certain, on the basis of general de-
velopmental screening and/or available psychometric
testing with standardized tools, that the child also has
GDD or intellectual disability, then the PCP might order
high-resolution karyotype and DNA testing for fragile X
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syndrome. If the child has clinical features (history, fam-
ily history, physical examination) that are characteristic
of a specific genetic or neurologic disorder that can be
easily confirmed by a specific laboratory test, then the
PCP may want to proceed with that test. On the other
hand, the PCP may opt to refer the child to pediatric
subspecialists for assistance with an etiologic workup
and/or a search for coexisting conditions. Depending on
availability and the nature of the concern(s), the PCP
should consider a referral to a developmental pediatri-
cian, a geneticist, and/or a child neurologist.
104,296
See the
next section for a more extensive discussion of the com-
ponents of a comprehensive evaluation.
Step 8.2.b: Early Intervention/Early Childhood Education
Services
As soon as an infant or toddler is suspected of having a
delay or being at risk of a delay or developmental disor-
der such as an ASD, he should be referred immediately
to an early intervention program (a government-subsi-
dized public program designed to serve children with
special needs and/or developmental delays from