Autism spectrum disorder in children and adolescents: Evaluation and diagnosis

INTRODUCTION — Autism spectrum disorder (ASD) is a biologically based neurodevelopmental disorder characterized by persistent deficits in social communication and social interaction and restricted, repetitive patterns of behavior, interests, and activities.

The evaluation and diagnosis of ASD will be reviewed here. Surveillance and screening for ASD and the terminology, epidemiology, pathogenesis, clinical features, and management of ASD are discussed separately.

●(See "Autism spectrum disorder in children and adolescents: Surveillance and screening in primary care".)

●(See "Autism spectrum disorder (ASD) in children and adolescents: Terminology, epidemiology, and pathogenesis".)

●(See "Autism spectrum disorder in children and adolescents: Clinical features".)

●(See "Autism spectrum disorder in children and adolescents: Overview of management".)

ROLE OF PRIMARY CARE PROVIDER

●Early identification and clinical suspicion – Primary care providers can identify children at risk for ASD through routine developmental, behavioral, and ASD-specific surveillance and screening combined with clinical judgment. (See "Autism spectrum disorder in children and adolescents: Surveillance and screening in primary care" and "Developmental-behavioral surveillance and screening in primary care".)

ASD should be suspected in children with abnormalities in social interaction that are not better explained by impaired cognitive skills. The abnormal social interactions are due to limited social communication skills (eg, difficulty with social attention and dyadic conversation with a limited ability to understand another's perspective) as well as restricted, repetitive patterns of behavior, interests, and activities. (See 'Diagnostic criteria' below and "Autism spectrum disorder in children and adolescents: Clinical features", section on 'Terminology'.)

●Refer for comprehensive evaluation – Children who are identified as being at risk for ASD should be referred to a specialist (eg, developmental-behavioral pediatrician, child psychiatrist, child neurologist, (neuro)psychologist with expertise in ASD) for a comprehensive evaluation to establish the diagnosis [1-3]. Accurate and appropriate diagnosis usually requires a clinician who is experienced in the diagnosis and treatment of ASD, ideally with input from multiple disciplines to assess core symptoms, functional impairment, severity, and comorbid conditions [1,2,4-9]. (See 'Comprehensive evaluation' below.)

●Make the initial diagnosis – Although most children will need to see a specialist (eg, developmental-behavioral pediatrician, child psychiatrist, child neurologist, [neuro]psychologist), for a diagnostic evaluation, general pediatricians and child psychologists comfortable with application of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition Text Revision criteria for ASD can make an initial clinical diagnosis. Having a clinical diagnosis may facilitate initiation of services [10].

The primary care provider can make a diagnosis of ASD using first- and second-tier screening instruments, which are discussed separately, if they have adequate clinical experience and confidence in the veracity of the evaluation they can perform. It is important to check local educational system and insurance requirements for the given diagnosis to qualify the youth for treatment. (See "Autism spectrum disorder in children and adolescents: Screening tools".)

●Refer for intervention pending diagnosis – Primary care providers who suspect that a child has ASD should refer the child for developmental-behavioral services pending the comprehensive evaluation. In the United States, services are provided through Early Intervention (for children <36 months of age) or the public school system (for children ≥36 months of age). State-specific contact information for Early Intervention is available through the Centers for Disease Control and Prevention.

The primary care provider also can refer the child for other interventions that the family can provide while awaiting the comprehensive evaluation. The type of intervention varies depending on the caregivers' concerns [11,12]. Examples of concerns for which interventions not specific to ASD are available are listed below. Such interventions may support the family pending definitive diagnosis.

•Difficulty with communication – For children who have difficulty communicating, the provider can discuss using visual supports, avoiding the use of abstract terms (eg, metaphors, idioms), and providing concrete and explicit instructions.

•Atypical language – The provider can suggest that the caregivers use picture books to foster joint attention, name objects, and tell stories. Caregivers can also be encouraged to provide an ongoing description of their activities for the child. They should be encouraged to seek opportunities for the child to hear books read aloud at the local public library. (See "Expressive language delay ("late talking") in young children", section on 'Prevention'.)

•Global developmental delay – The provider can encourage language and cognitive development through social opportunities and language stimulation as described in the preceding bullet.

•Delays in socialization – The provider can make a referral to a supervised community play group or social-skills group (in addition to a referral for developmental-behavioral services).

•Difficulty with routine – For children who have difficulty completing routine daily activities or transitioning between activities, the provider can suggest using a picture schedule to remind children what to do when as well as when they can expect activities that they enjoy (eg, screen time).

•Challenging behaviors – The provider can refer caregivers who have difficulty managing challenging behaviors (eg, hyperactive, anxious, aggressive behaviors) to an evidence-based caregiver training program, such as Triple P (Positive Parenting Programs), Parent-Child Interaction Therapy, or the Incredible Years [13].

•Temperament – Caregivers may have differing abilities to tolerate challenging behaviors. In such cases, the provider can discuss the concept of temperament, administer a temperament scale (eg, the Carey Temperament Scales [available for purchase] or one of the scales available from The Preventive Ounce [available with paid family membership]) to the child and caregiver, and discuss "goodness of fit" [14,15].

COMPREHENSIVE EVALUATION — The reference standard for evaluating a child for ASD consists of a comprehensive assessment. A comprehensive assessment includes a multidisciplinary team with a lead clinician who has expertise in the diagnosis and management of ASD (eg, a developmental-behavioral pediatrician, child psychiatrist, child neurologist, or [neuro]psychologist), a speech and language pathologist, and an educator [1-3,5-9,16]. Each of the team members may evaluate the child at a single coordinated visit or individually at different visits. Video visits may facilitate observation of the child in natural social settings.

Goals — The goals of the comprehensive evaluation include [1,2,8,16,17]:

●To determine if the child's symptoms meet established diagnostic criteria for ASD (see 'Diagnostic criteria' below)

●To determine the child's level of functioning and neurodevelopmental profile of strengths and weaknesses, which will affect the individualized management plan (see 'Ancillary testing' below and 'Assessment of severity' below)

●To determine whether the child has ASD, another condition (table 1), or ASD and an associated condition (eg, associated intellectual or language impairments, medical or genetic conditions, or other neurodevelopmental, mental, or behavioral disorders) (see 'Ancillary testing' below and 'Differential diagnosis' below and 'Evaluation for associated conditions' below)

Components

History — The history is usually obtained from the parents or caregivers. Teachers, childcare professionals, and therapists also can provide critical information [18].

Important aspects of the history include [1,4,8,19]:

●Early ASD symptoms

•Review of the developmental history, with particular attention to early social-emotional and language milestones, play skills and behaviors, behavior, and loss of skills; it is particularly useful to ask about the child's interest in playing with other children, their ability to copy what other children do, and whether or not their play behaviors mimic social events or social situations. All of these behaviors are typically absent or limited in children with ASD (table 2).

•Specific examples of early social and communication behaviors include responsiveness when called by name, shared enjoyment with caregiver, use of eye contact during communication, and use of pointing as a means of communication. All of these behaviors are typically missing in the child with ASD. Older children with ASD commonly struggle with taking turns in a play interaction or conversation, fail to regulate their social interactions using eye contact, and show limited nonverbal communication skills such as changes in facial expressions, gestures, and intonation.

●ASD symptoms in older children (vary with developmental level at presentation):

•Caregiver concerns regarding hearing, vision, and speech/language

-Difficulty having back-and-forth conversation

-Ability to understand ambiguous nonliteral communication (eg, metaphors, sarcasm, expressions like "it's raining cats and dogs")

•Specific information about current social and communicative behaviors (table 3)

-Quality of attachment to family members (Does the child share warm interactions with their primary caregivers or turn to them for help and assistance?)

-Level of interest in socializing with others (Does the child show an interest in socializing with adults or peers? If they do, are the social bids atypical?)

-Capacity to socialize successfully, using appropriate social attention, social communication behaviors, and ability to understand another's perspective (Is the child able to respond to the social bids of others? Does the child make social bids to adults or peers? Are these social bids designed only to satisfy wants and needs, or do the social bids also imply an interest in a social interaction? Are the social bids scripted, odd, or unusual?)

-Development of peer relationships and friendships (Is the child able to identify a friend? Is the child able to make the distinction between who is a friend versus who is an acquaintance or a stranger? Does the child show an interest in socializing with peers? Is the child able to develop peer relations at age-level? Is the child able to maintain friendships?)

-Ability to infer another person's feelings, intentions, or beliefs (Does the child make errors in interpreting the intentions and feelings of others? Do these errors occur in real-time social interactions or also when looking at pictures or at story books?)

-Capacity for self-awareness and perspective-taking

-Level of insight into social and behavioral problems and the child's role in relationships

•History of repetitive, ritualized, or stereotyped behaviors (eg, hand flapping) or increased or decreased response to or unusual interest in sensory stimuli:

-Stereotypy/repetitive behaviors, such as hand-flapping, spinning the self or objects, rocking behaviors

-Insistence on sameness and routines; inflexible behavior; frequent tantrums and trouble tolerating transitions or changes in routines

-Patterns of special interest and leisure activities (eg, very specific and often mechanical interests such as trains, subway lines, vacuum cleaners, ceiling fans)

-Unusual visual behavior or preoccupation with parts of toys

•History of common associated conditions:

-Significant disturbance in regulation, including eating (including pica), sleep, or toileting

-Self-injury

-History of possible seizures

-Depression (in adolescents and adults)

-Symptoms of anxiety

-Learning difficulty

-Attentional challenges

●Family history – A three-generation family history should be reviewed for ASD and conditions that often are associated with ASD, coexist with ASD, or share symptoms with ASD [1,8]. ASD has a strong genetic component. (See "Autism spectrum disorder (ASD) in children and adolescents: Terminology, epidemiology, and pathogenesis" and 'Differential diagnosis' below.)

•ASD (including previously used terms, such as pervasive developmental disorder, autism, Asperger syndrome, childhood disintegration syndrome, pervasive developmental disorder not otherwise specified)

•Intellectual disability

•Language delay

•Learning and attentional disorders (eg, attention deficit hyperactivity disorder)

•Seizures

•Tic disorders

•Tuberous sclerosis complex, fragile X syndrome, Rett syndrome, Angelman syndrome, Prader-Willi syndrome, Smith-Lemli-Opitz syndrome

•Obsessive-compulsive disorder

•Anxiety

•Extreme shyness, social phobia, or selective mutism

•Mood disorders

•Schizophrenia

●Psychosocial history – The psychosocial history should include information regarding the family supports and stresses, which may affect management. Exposure to trauma, early deprivation, and attachment disorder can result in symptoms that overlap with ASD but need to be differentiated from ASD because they require treatment separate from the treatment for ASD [20]. (See 'Differential diagnosis' below.)

Examination — Extra time should be allotted for the examination because communication deficits and behavioral symptoms may limit cooperation. Strategies to facilitate examination are discussed separately. (See "Autism spectrum disorder in children and adolescents: Overview of management", section on 'Office visits'.)

Important aspects of the physical examination include [1]:

●Weight – Restricted, repetitive dietary patterns can result in poor weight gain or obesity. (See "Autism spectrum disorder in children and adolescents: Clinical features".)

●Head circumference, including head circumference trajectory if previous measurements are available. (See "Autism spectrum disorder in children and adolescents: Clinical features".)

•Children with ASD often have early acceleration of head growth, followed by stabilization [21]. Approximately one-fourth of children with isolated ASD have head circumference greater than the 97^th percentile [4,22]. (See "Autism spectrum disorder in children and adolescents: Clinical features", section on 'Macrocephaly'.)

-Individuals with ASD and macrocephaly may have mutations in the PTEN gene, associated with increased risk of hamartomatous tumor syndromes [23]. (See "PTEN hamartoma tumor syndromes, including Cowden syndrome", section on 'Autism spectrum disorders and macrocephaly'.)

•Approximately 15 percent of children with ASD have microcephaly; microcephaly usually occurs in patients with associated conditions (eg, Angelman syndrome, Smith-Lemli-Opitz syndrome) [24].

●Wood lamp examination – May demonstrate the hypopigmented macules of tuberous sclerosis complex (picture 1), an associated condition. (See "Tuberous sclerosis complex: Clinical features".)

●Examination for dysmorphic features or neurodevelopmental findings of clinical syndromes associated with ASD (table 4).

●Examination of muscle tone and reflexes – Children with ASD can have mild hypotonia. (See "Autism spectrum disorder in children and adolescents: Clinical features", section on 'Motor deficits'.)

●Focal neurologic findings, such as asymmetry in tone or reflexes, require further neurologic evaluation and possible neuroimaging. (See 'Other testing as indicated' below.)

Diagnostic tools — Diagnostic tools are used to gather behavioral data in a structured and consistent manner, either through an interview with the caregivers or (more commonly) by making direct observations of the child. Diagnostic tools are used in conjunction with clinical judgment to make a diagnosis of ASD; they should not be used in isolation [1,2,4]. Diagnostic tools for ASD generally are administered by a specialist; most require intensive training for administration. In the United States, use of a diagnostic tool may be required for access to intensive behavioral interventions (eg, Applied Behavior Analysis) from the child's insurance plan.

A number of diagnostic tools are available, but their accuracy has not been well studied (table 5) [17,25]. Tools that are recommended in national guidelines include [1,4,7-9]:

●Autism Diagnostic Interview-Revised (ADI-R)

●Autism Diagnostic Observation Schedule-2^nd edition (ADOS-2)

Valid scoring of the ADOS requires that it be performed in person and without physical barriers, face masks, or other personal protective equipment [26].

●Childhood Autism Rating Scale 2^nd edition (CARS-2)

The CARS-2 may be suitable for a primary care clinician if a comprehensive evaluation is not available or the wait time is excessive.

●Developmental Dimensional and Diagnostic Interview (3di), used predominantly outside the United States

●Diagnostic Interview for Social and Communication Disorder (DISCO), used predominantly outside the United States

●Gilliam Autism Rating Scale (GARS)

In their practice, the authors and section editors of this topic use the ADI-R, ADOS-2, CARS-2, and Social Responsiveness Scale, Second edition [27,28]. Other diagnostic instruments and rating scales are less sensitive and specific [17,25,29].

In a systematic review of observational studies evaluating diagnostic accuracy in children <6 years of age who underwent multidisciplinary evaluation for ASD (the reference standard), no studies evaluating GARS, 3di, or DISCO met inclusion criteria [17]. Among studies of ADI-R, CARS, and ADOS, there was substantial variation in sensitivity and specificity, likely related to differences in study populations and methodology. There were too few studies to permit meaningful direct comparison. However, when the summary statistics were compared, ADOS was most sensitive (94 percent compared with 80 percent for CARS and 52 percent for ADI-R). The three tools had similar specificity (ranging from 80 to 88 percent).

Diagnostic tools for ASD must be used in conjunction with clinical judgment for a number of reasons. The administration protocols that are used in research studies may not be achievable in clinical practice. In the studies included in the systematic review, ASD was diagnosed according to criteria from the Diagnostic and Statistical Manual of Mental Disorders (DSM), Fourth edition or earlier classifications that do not directly correlate with DSM, Fifth Edition Text Revision criteria [17]. In addition, the versions of the tools evaluated in published studies may have been updated after publication.

Ancillary testing — Ancillary testing is necessary to corroborate and confirm the diagnosis of ASD, to differentiate ASD from other conditions that mimic ASD, and to identify conditions that occur with ASD. In addition, ancillary testing helps to determine the child's level of impairment and identify targets for therapeutic intervention.

Ancillary testing generally includes [4,5,8,19]:

●Speech, language, and communication assessment – The speech and language assessment provides a profile of language and communication skills and may differentiate ASD from developmental language disorder, language-based learning disorder, and pragmatic language or social communication disorder. (See 'Differential diagnosis' below.)

The speech and language evaluation includes assessment of [19]:

•Formal language functions (eg, vocabulary, grammar, syntax)

•Prosodic features and intonation (eg, rate, rhythm, volume, emotional expressiveness)

•Pragmatic language/social communication skills (eg, nonverbal communication [facial expressions, gestures, body language, prosody], nonliteral language, communication with dual meanings [eg, metaphor, humor, sarcasm], content of conversations [appropriateness of topic for the social situation], ability to stay on topic [contingency and topic maintenance])

Pragmatic language tests are subject to observer interpretation. Individuals with ASD may perform successfully in the 1:1 testing situation but not in real-time situations (eg, classroom discussion, peer interaction).

●Developmental/intelligence testing with separate estimates for verbal and nonverbal skills. It is also important to perform an academic evaluation to assess reading, writing, and math skills. In the United States, the academic evaluation may be performed in the public school system rather than during the comprehensive medical evaluation, depending upon insurance coverage.

●Assessment of adaptive skills to document associated intellectual disability and to help establish priorities for treatment planning; functional impairment is one of the diagnostic criteria for both ASD and intellectual disability. In addition, in the United States, overall levels of function determine eligibility for services in many states. (See 'Diagnostic criteria' below and "Intellectual disability (ID) in children: Clinical features, evaluation, and diagnosis", section on 'Diagnosis'.)

●Sensorimotor and/or occupational therapy evaluation to evaluate the extent and type of sensory sensitivities and for low tone and coordination problems.

●Vision and hearing assessment (if not already performed).

●Lead testing (if not already performed).

●Other tests – Ancillary testing may also include specific tests for certain conditions associated with ASD as indicated by the initial clinical evaluation. (See 'Evaluation for associated conditions' below and 'Differential diagnosis' below.)

DIAGNOSIS

Diagnostic criteria — The diagnosis of ASD is made clinically in children who meet established diagnostic criteria for ASD based on history and observation of behavior. There are two major sets of diagnostic criteria, both of which center on atypical social communication and interaction and restricted, repetitive patterns of behavior, activities, and interests: the Diagnostic and Statistical Manual of Mental Disorders (DSM) and the International Disease Classification (ICD).

●DSM, Fifth edition criteria – According to the DSM, Fifth edition Text Revision (DSM-5-TR) criteria, a diagnosis of ASD requires all of the following [30]:

•Persistent deficits in social communication and social interaction in multiple settings; demonstrated by deficits in all three of the following (either currently or by history):

-Social-emotional reciprocity (eg, failure to produce mutually enjoyable and agreeable conversations or interactions because of a lack of mutual sharing of interests, lack of awareness or understanding of the thoughts or feelings of others)

-Nonverbal communicative behaviors used for social interaction (eg, difficulty coordinating verbal communication with its nonverbal aspects [eye contact, facial expressions, gestures, body language, and/or prosody/tone of voice])

-Developing, maintaining, and understanding relationships (eg, difficulty adjusting behavior to social setting, lack of ability to show expected social behaviors, lack of interest in socializing, difficulty making friends even when interested in having friendships)

•Restricted, repetitive patterns of behavior, interests, or activities; demonstrated by ≥2 of the following (either currently or by history):

-Stereotyped or repetitive movements, use of objects, or speech (eg, stereotypies such as rocking, flapping, or spinning; echolalia [repeating parts of speech]; repeating scripts from movies or prior conversations; ordering toys into a line)

-Insistence on sameness, unwavering adherence to routines, or ritualized patterns of verbal or nonverbal behavior (eg, difficulty with transitions, greeting rituals, need to eat the same food every day)

-Highly restricted, fixated interests that are abnormal in strength or focus (eg, preoccupation with certain objects [trains, vacuum cleaners, or parts of trains or vacuum cleaners]); perseverative interests (eg, excessive focus on a topic such as dinosaurs or natural disasters)

-Increased or decreased response to sensory input or unusual interest in sensory aspects of the environment (eg, adverse response to particular sounds; apparent indifference to temperature; excessive touching/smelling of objects)

•The symptoms must impair function (eg, social, academic, completing daily routines).

•The symptoms must be present in the early developmental period. However, they may become apparent only after social demands exceed limited capacity; in later life, symptoms may be masked by learned strategies.

•The symptoms are not better explained by intellectual disability or global developmental delay.

ASD may occur with or without medical, genetic, neurodevelopmental, mental, or behavioral problems (eg, intellectual impairment, language impairment, epilepsy, fetal valproate or alcohol exposure). The presence or absence of these problems are specified as part of the DSM-5-TR diagnosis of ASD (eg, ASD with accompanying intellectual impairment, ASD without accompanying language impairment) [30]. Some accompanying conditions are identified during the comprehensive evaluation; others may require additional testing. (See 'Evaluation for associated conditions' below.)

The clinical features of ASD, including examples of deficits and abnormal functioning in these domains, are discussed separately. (See "Autism spectrum disorder in children and adolescents: Clinical features".)

●ICD 11^th Revision criteria – The ICD 11^th Revision (ICD-11) criteria for the diagnosis of ASD are provided in ICD-11 for Mortality and Morbidity Statistics [31].

Assessment of severity — In conjunction with an adaptive scale (eg, Vineland Adaptive Behavior Scale, Adaptive Behavior Assessment System), we use the DSM-5-TR classification to specify the severity level of ASD, recognizing that severity may vary with context and over time [30]. Severity should be assessed separately for each domain, as indicated below. Co-occurring intellectual impairment often accounts for the differences in levels of severity.

●Social communication/interaction

•Level 1 ("Requiring support") – Noticeable impairment without support; difficulty initiating social interactions, atypical or unsuccessful responses to social overtures; decreased interest in social interactions; failure of turn-taking in conversation; failure to generate responses or topics appropriate to the context; unsuccessful or odd attempts to make friends.

A child with ASD and level 1 social communication/interaction may be able to successfully communicate basic intentions and needs using words but may do so in a scripted manner that does not include any nonverbal communication behaviors (eg, changes in facial expression, use of eye contact, use of gestures).

•Level 2 ("Requiring substantial support") – Marked deficits in communication; impairments apparent even with supports; limited initiation of social interactions; reduced/abnormal response to social overtures.

•Level 3 ("Requiring very substantial support") – Severe impairments in functioning; very limited initiation of social interactions; minimal response to social overtures from others.

Examples of social communication/interaction that requires very substantial support include:

-Nonexistent communication (the child makes no attempts to share thoughts or interests or to make requests)

-Communication that consists only of physical gestures (eg, takes an adult by the hand to lead them to a desired object or activity without accompanying eye contact or spoken language)

-Communication that consists of words that are repeated from other contexts and have no relevance to the current context (eg, echolalia)

●Repetitive/restricted behavior

•Level 1 ("Requiring support") – Behaviors significantly interfere with function; difficulty switching between activities; independence limited by problems with organization and planning.

In children with ASD and level 1 repetitive/restricted behavior, the behavior may manifest as a specific interest (eg, trains, vacuum cleaners), a general topic (eg, dinosaurs, natural disasters), or an age-appropriate interest (eg, collecting cards). However, the perseverative interest takes up the majority of the child's recreational time and interferes with other activities. In addition, the child often experiences distress or frustration when not allowed to pursue the interest [32].

•Level 2 ("Requiring substantial support") – Behaviors sufficiently frequent to be obvious to casual observer; behaviors interfere with function in a variety of settings; distress and/or difficulty changing focus or action.

•Level 3 ("Requiring very substantial support") – Behaviors markedly interfere with function in all spheres; extreme difficulty coping with change; great distress/difficulty changing focus or action.

Examples of repetitive/restricted behavior that requires very substantial support include:

-Rocking or spinning the body, spinning objects, flapping the hands while rocking, or visual self-stimulatory behaviors associated with spinning or rocking objects or the self

-Engaging in unusual sensory exploration such as regarding hands or objects closely, sniffing or mouthing objects

-Rigid adherence to routines during play or adaptive tasks that interferes with functional activities (eg, socializing)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of ASD includes a number of conditions that impair social communication or social interaction and/or are associated with stereotypic movements (table 1). In some cases, these conditions are the cause of the ASD-like symptoms and the child does not have ASD; in other cases, the conditions co-occur with ASD [30,33-35]. In co-occurring cases, the co-occurring condition should not better explain the symptoms. An important function of the comprehensive multidisciplinary evaluation is to determine whether the child has ASD, another condition, or ASD and another condition. (See 'Goals' above.)

It may be particularly difficult to distinguish co-occurring conditions from ASD in young children. Young children may need to be followed over time before a definitive diagnosis can be made. Similarly, it can be difficult to distinguish co-occurring conditions from ASD in older children who have a dual diagnosis such as attention deficit hyperactivity disorder (ADHD) and anxiety, ADHD and a language impairment, or social anxiety disorder, particularly in children with normal or superior intelligence.

A history of reduced or inconsistent social reciprocity generally distinguishes ASD from the conditions in the differential diagnosis. The impairment in social reciprocity has to be best explained by ASD and not by the co-occurring condition.

Pending definitive diagnosis, primary care providers who suspect that a child has ASD should refer the child for developmental-behavioral services. (See 'Role of primary care provider' above.)

Conditions to be considered in the differential diagnosis of ASD in children include [1,6,8]:

●Global delay/intellectual disability – Global developmental delay or intellectual disability may be difficult to distinguish from ASD, particularly in young children and in those with profound cognitive impairment. Cognitive deficits are difficult to assess in the young, nonverbal child, and severe deficits may be associated with repetitive behaviors and mixed expressive/receptive language delay [36]. In addition, intellectual disability is common among children with ASD [37,38]. (See "Intellectual disability (ID) in children: Clinical features, evaluation, and diagnosis" and "Autism spectrum disorder in children and adolescents: Clinical features", section on 'Intellectual impairment'.)

The social responsiveness and communication efforts of children with isolated global developmental delay/intellectual disability are usually appropriate for their developmental level, whereas those of children with ASD are aberrant for their developmental level [8]. Clinical features that are more characteristic of ASD and coexisting global developmental delay than isolated global developmental delay/intellectual disability include impaired nonverbal behaviors and lack of social/emotional reciprocity [39].

●Intellectual giftedness – Intellectual giftedness can mimic ASD, particularly if the child with intellectual giftedness has comorbid attention deficit hyperactivity disorder (ADHD), learning disability, or anxiety. In contrast to children with ASD, children with social awkwardness related to intellectual giftedness typically enjoy social interaction, have normal pragmatic language skills, and can explain their intense interests, which are functional and varied. (See "Children who are gifted: Characteristics and identification".)

●Social (pragmatic) communication disorder – Similar to ASD, social (pragmatic) communication disorder is characterized by persistent difficulties in the social use of verbal and nonverbal communication (eg, sharing information, changing communication style to match the context or listener, following the rules of conversation and storytelling, making inferences, understanding nonliteral or ambiguous meanings of language [eg, idioms, humor]) [40]. It is distinguished from ASD by the absence of restricted, repetitive patterns of behavior, interests, or activities.

●Language disorder – In contrast to children with ASD, children with developmental language disorder have normal reciprocal social interactions, normal desire and intent to communicate, and appropriate imaginative play [8,41]. (See "Etiology of speech and language disorders in children", section on 'Language disorders'.)

●Language-based learning disorder – In contrast to children with ASD, children with language-based learning disorders have normal reciprocal social interactions, normal desire and intent to communicate, and appropriate imaginative play. Children with language-based learning disorder have difficulty or delay in processing content, but their pragmatics (ie, ability to initiate and sustain a conversation) are more typical than those of children with ASD. In addition, the intent to communicate in children with language-based learning disorder is present, even though the competency may be lacking. (See "Specific learning disorders in children: Clinical features", section on 'Language-based learning disorder'.)

●Nonverbal learning disorder – Children with nonverbal learning disorder may have impaired social reasoning, strong rote skills, and well-developed basic language skills, similar to some children with ASD without intellectual or language impairment. However, children with nonverbal learning disorder lack restricted, repetitive patterns of behavior, interests, or activities and usually have milder impairments in social skills and pragmatic language than those with ASD. (See "Specific learning disorders in children: Clinical features", section on 'Nonverbal learning disorder'.)

●Hearing impairment – In contrast to children with ASD, children with hearing impairment usually have normal reciprocal social interactions, imaginative play, normal eye-to-eye gaze, and facial expressions indicative of their intention to communicate [41].

●Landau-Kleffner syndrome – Landau-Kleffner syndrome (LKS, also called acquired epileptic aphasia) is characterized by the loss of previously established language milestones, inability to comprehend the spoken word, and seizures or an epileptiform electroencephalogram. Children with LKS usually develop normally until approximately three to six years of age (in contrast to ASD, in which symptoms usually are present in the early developmental period but may not manifest until social demands exceed capacities). LKS typically begins with the children behaving as if they were deaf (auditory verbal agnosia). Difficulties with expressive language also occur with time, but cognitive function usually remains normal. (See "Epilepsy syndromes in children", section on 'Developmental and epileptic encephalopathy with spike-wave activation in sleep (DEE-SWAS)'.)

●Rett syndrome – Rett syndrome is a neurodevelopmental disorder that occurs almost exclusively in females. Affected patients initially develop normally, then gradually lose speech and purposeful hand use sometime after 18 months of age. Most cases of Rett syndrome result from mutations in the MECP2 gene. Characteristic features of Rett syndrome include deceleration of head growth (in contrast to acceleration of head growth, which occurs in ASD) and stereotypic hand movements. (See "Rett syndrome: Genetics, clinical features, and diagnosis", section on 'Classification and major features'.)

●Fetal alcohol syndrome – Similar to children with ASD, children with fetal alcohol syndrome (FAS) may have deficits in social and neurobehavioral skills. Characteristic facial features of FAS (ie, short palpebral fissures, thin vermillion border, and smooth philtrum (picture 2)) distinguish FAS from ASD. Although microcephaly is more common in children with FAS than ASD, microcephaly is not necessary for the diagnosis of FAS. (See "Fetal alcohol spectrum disorder: Clinical features and diagnosis", section on 'Clinical features'.)

●Attachment disorder – Similar to children with ASD, children with severe early deprivation or reactive attachment disorder may have abnormalities in social interaction, communication, and behavior. However, there usually is a history of severe neglect or mental health issues in the caretaker [42]. In addition, the social deficits of children with attachment disorder tend to improve in response to an appropriate caregiving environment.

●Attention deficit hyperactivity disorder – Children with ADHD may have impaired social function, though the impairments can be milder than those in children with ASD. In contrast to children with ASD, those with ADHD usually have normal pragmatic language skills, nonverbal social behavior, and imaginary play [43,44]. (See "Attention deficit hyperactivity disorder in children and adolescents: Clinical features and diagnosis", section on 'Clinical features'.)

●Anxiety disorder – Anxiety disorder (includes social anxiety disorder, specific phobia, and selective mutism) has behavioral features that overlap with ASD, particularly when it occurs in combination with ADHD or language impairment. To the extent that it can be determined, individuals with anxiety disorder find their symptoms distressing, whereas individuals with ASD typically do not. However, children with ASD frequently experience anxiety symptoms that they find distressing. In contrast to children with ASD, children with primary anxiety disorders usually have normal nonverbal social behavior and imaginary play [43]. The defining feature of social anxiety disorder is fear of being judged, negatively evaluated, or rejected in a social or performance situation, rather than impairment in social interaction. (See "Anxiety disorders in children and adolescents: Epidemiology, pathogenesis, clinical manifestations, and course" and "Anxiety disorders in children and adolescents: Assessment and diagnosis".)

●Obsessive-compulsive disorder – Obsessive-compulsive disorder (OCD) has behavioral features that overlap with ASD. To the extent that it can be determined, individuals with OCD find their obsessions distressing, whereas individuals with ASD typically are unaware of their perseverations [45]. However, children with ASD may have symptoms of OCD that they find distressing. In addition, children with OCD typically have normal social and communication/language skills. (See "Obsessive-compulsive disorder in children and adolescents: Epidemiology, pathogenesis, clinical manifestations, course, assessment, and diagnosis".)

●Stereotypic movement disorder – Similar to children with ASD, children with stereotypic movement disorder have repetitive, purposeless motor behaviors (eg, hand flapping, head banging) that may result in self-injury [46,47]. However, unlike children with ASD, children with stereotypic movement disorder typically have normal social and communication/language skills. (See "Hyperkinetic movement disorders in children", section on 'Stereotypies'.)

●Tic disorder/Tourette syndrome – Similar to children with ASD, children with tic disorder or Tourette syndrome have sudden, brief, intermittent movements or utterances. Children with tic disorder or Tourette syndrome usually have normal social and communication/language skills. Atypical social interactions in children with tic disorder or Tourette syndrome are typically due to coexistent anxiety, impulsivity, and/or poor self-esteem related to tics. (See "Hyperkinetic movement disorders in children", section on 'Tic disorders' and "Tourette syndrome: Pathogenesis, clinical features, and diagnosis", section on 'Clinical features'.)

EVALUATION FOR ASSOCIATED CONDITIONS — Additional evaluation may be necessary to identify comorbid conditions that have implications for treatment or genetic counseling [5,7]. The evaluation for associated conditions usually includes genetic testing; other tests are individualized according to the history and clinical presentation [4,8]. The yield of additional testing in the absence of clinical indications is low [48].

Genetic testing

●Initial genetic tests – Consultation with or referral to a clinical geneticist is suggested to determine an individualized testing strategy that optimizes identification and exclusion of genetic conditions with medical consequences while considering out-of-pocket costs to the patient's family. The most appropriate tests for a particular child with ASD may vary with clinical features (eg, dysmorphic features, extended family history). If genetics consultation is not available, standard testing may include chromosomal microarray (CMA) and deoxyribonucleic acid (DNA) analysis for fragile X, whether or not the child has dysmorphic features. Karyotype is warranted if a balanced translocation is suspected (eg, history of ≥2 miscarriages) because CMA does not detect balanced translocations [49]. However, truly balanced de novo translocations are rare [50].

Identification of a genetic diagnosis may prevent associated medical complications for the child, provide specific information about recurrence risk for family members, and prevent further search for complementary and alternative diagnoses and treatments, which are often nonevidence based and expensive. It also may provide emotional relief for the caregivers and can be crucial to the therapeutic alliance. However, few studies have evaluated the effect of genetic testing on such outcomes and it is unclear whether or not genetic testing affects health outcomes [51].

Consultation with a clinical geneticist also may be necessary for interpretation of CMA results. Interpretation of microarray data is complicated by the identification of novel and/or recurrent copy-number variants of unknown significance. Nonetheless, CMA has the highest detection rate among clinically available genetic tests for patients with ASD (excluding whole-exome sequencing, which may be costly and not covered by all insurance carriers) [52-55]. (See "Tools for genetics and genomics: Cytogenetics and molecular genetics" and "Next-generation DNA sequencing (NGS): Principles and clinical applications".)

A recognizable disorder is found in a minority of cases, usually in patients with comorbid global developmental delay or intellectual disability. In a cohort of 933 patients who underwent genetic testing for a diagnosis of ASD, karyotype was abnormal in 2 percent, fragile X testing was abnormal in 0.5 percent, and array comparative genomic hybridization identified abnormal deletions or duplications in 7 percent [52]. In another population-based sample of 258 consecutively diagnosed unrelated children with ASD, CMA yielded a molecular diagnosis in 9.3 percent [54]. Among the 95 children who underwent both CMA and whole-exome sequencing, the yield of whole-exome sequencing was similar to that of CMA (8.4 percent) and the combined yield of CMA and whole-exome sequencing was 15.8 percent. Molecular diagnosis was achieved more often in children with more severe dysmorphology, suggesting that it may be possible to identify children with the greatest likelihood of genetic diagnosis [56].

Our approach to genetic testing of children with ASD is consistent recommendations of the American College of Medical Genetics and Genomics and the International Standards for Cytogenomic Arrays Consortium [49,57-61].

●Other genetic tests as clinically indicated – We obtain other types of genetic testing as clinically indicated in children with dysmorphic features, microcephaly, macrocephaly, cognitive impairment, suspicious medical or family history, or in cases where prenatal genetic counseling is desired [57,62]. Consultation with, or referral to, a clinical geneticist can be helpful in determining the appropriate studies.

Specific testing should be guided by the clinical findings. As examples:

•Testing for the X-linked MECP2 Rett mutation may be warranted for patients, particularly females, with a history of significant developmental regression [4,63]. (See "Rett syndrome: Genetics, clinical features, and diagnosis".)

•Testing for mutations in the PTEN gene should be completed for patients with ASD and macrocephaly (greater than 2.5 standard deviations above the mean for age and sex) to rule out hamartomatous tumor syndromes (eg, Proteus syndrome, Cowden syndrome, including Bannayan-Riley-Ruvalcaba syndrome) [57]. (See "PTEN hamartoma tumor syndromes, including Cowden syndrome", section on 'Autism spectrum disorders and macrocephaly'.)

Other testing as indicated

●Metabolic testing – Disorders of amino acid, carbohydrate, purine, peptide, and mitochondrial metabolism account for <5 percent of cases of ASD [4,64].

We obtain metabolic testing in children with ASD and symptoms or signs of a metabolic disorder, including [4,48,64,65]:

•Lethargy, limited endurance (particularly if associated with mild illness)

•Hypotonia

•Recurrent vomiting and dehydration

•Early seizure

•Dysmorphic or coarse features

•Intellectual disability (or if intellectual disability cannot be excluded)

•Developmental regression

•Hearing impairment

•Vision impairment

•Unusual odors

•Specific food intolerance (eg, protein)

•Inadequate or questionable adequate newborn screen

The evaluation is individualized according to the clinical features. Consultation with a clinical geneticist is suggested. (See "Inborn errors of metabolism: Epidemiology, pathogenesis, and clinical features" and "Metabolic emergencies in suspected inborn errors of metabolism: Presentation, evaluation, and management".)

In observational studies, in the absence of signs or symptoms of metabolic disease, metabolic testing has low yield [48,57,66,67].

●Neuroimaging – We make decisions about neuroimaging in children with ASD on a case-by-case basis. In observational studies, the yield of magnetic resonance imaging is low in children with ASD and no other neurologic findings (eg, intellectual disability, abnormal neurologic examination, seizures, headache, focal neurologic findings) [48,68].

●Electroencephalogram – We obtain electroencephalography (EEG) in children with ASD only if warranted by history or physical examination, specifically for clinical seizures, unusual episodes, or behaviors frankly suggestive of seizures, and to exclude Landau-Kleffner syndrome (acquired epileptic aphasia) in children with regression in language skills [1,4]. Among children with ASD and staring spells, EEG rarely yields clinically significant findings [69] and thus is not routinely recommended. (See 'Differential diagnosis' above and "Epilepsy syndromes in children", section on 'Developmental and epileptic encephalopathy with spike-wave activation in sleep (DEE-SWAS)'.)

Tests that are not indicated — Tests for yeast metabolites, gut permeability, heavy metals (other than lead), trace elements, micronutrients, and immune abnormalities are not indicated, since there are no empiric data to support such analyses [4].

FOLLOW-UP — Follow-up with the diagnosing clinician is recommended within one to six months of initial diagnosis to address behavioral, environmental, and other developmental concerns [4]. Although it is not necessary to repeat the entire diagnostic evaluation, reassessment of developmental skills may be helpful because relatively small changes can affect the impact of ASD in young children. Reassessment of developmental skills, particularly social skills, provides an important measure of responsiveness to therapies and diagnostic stability. Reassessment visits should also be used to check on the emotional and practical response of the family to the diagnosis and their ability to meet the needs of their child as successfully as possible.

In addition, the primary care clinician should continue to see the patient every 6 to 12 months. Long-term support is critical for children with ASD and their families [4]. (See "Autism spectrum disorder in children and adolescents: Overview of management", section on 'Family support' and "Children and youth with special health care needs".)

RESOURCES — The Centers for Disease Control and Prevention's "Learn the Signs. Act Early." website provides information and resources for health care providers to improve early identification of children with ASD, including a video library of children with ASD and typically developing children and training modules regarding ASD screening, diagnosis, and communicating concerns.

Within the patient's capacity to understand, discussions about disclosing the diagnosis to the patient should begin early. Resources to aid clinicians and families in disclosure discussions are available from the:

●Asperger/Autism Network

●Interactive Autism Network

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Autism spectrum disorder".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient education" and the keyword[s] of interest.)

●Basics topic (see "Patient education: Autism spectrum disorder (The Basics)")

●Beyond the Basics topic (see "Patient education: Autism spectrum disorder (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Role of the primary care provider – In the evaluation and diagnosis of autism spectrum disorders (ASD), primary care providers generally identify children at risk and refer them for comprehensive evaluation and intervention pending diagnosis. Definitive diagnosis of ASD is usually made by a specialist (eg, developmental-behavioral pediatrician, child psychiatrist, child neurologist, (neuro)psychologist with expertise in ASD) in the context of a comprehensive evaluation. (See 'Role of primary care provider' above.)

●Goals of comprehensive evaluation – The goals of the comprehensive evaluation are (see 'Goals' above):

•To determine if the child's symptoms meet established diagnostic criteria for ASD (see 'Diagnostic criteria' above)

•To determine the child's level of function and neurodevelopmental profile of strengths and weaknesses

•To determine whether the child has ASD, another condition (table 1), or ASD and an associated condition (eg, intellectual or language impairments, medical or genetic conditions, or other neurodevelopmental, mental, or behavioral disorders) (see 'Ancillary testing' above and 'Evaluation for associated conditions' above)

●Components of evaluation

•History – The history is usually obtained from the parents or caregivers; teachers and therapists also can provide useful information. It focuses on early and current ASD symptoms; common associated conditions; family history of ASD, conditions associated with ASD, comorbid ASD, or conditions that share symptoms with ASD; and psychosocial history. (See 'History' above.)

•Physical examination – The physical examination is focused on consequences of restricted, repetitive dietary patterns and signs of associated conditions (eg, weight, head circumference, neurocutaneous findings, dysmorphic features, focal or asymmetric neurologic findings, abnormal neurodevelopmental findings). (See 'Examination' above.)

•Diagnostic tools – Diagnostic tools (table 5) are used in conjunction with the history and examination to make a diagnosis of ASD; they should not be used in isolation. Diagnostic tools for ASD generally are administered by a specialist. (See 'Diagnostic tools' above.)

•Ancillary testing – Ancillary testing is necessary to assess functional impairment, define the child's strengths and weaknesses for education planning, identify associated conditions (eg, intellectual impairment, language impairment), and evaluate conditions with symptoms that mimic ASD (table 1). Ancillary testing generally includes (see 'Ancillary testing' above):

-Speech language and communication assessment, with a focus on pragmatic language function (eg, nonverbal communication, nonliteral language, content of conversations, ability to stay on topic)

-Developmental/intelligence testing with separate estimates for verbal and nonverbal skills

-Sensorimotor and/or occupational therapy evaluation

-Vision, hearing, and lead testing (if not already performed)

-Specific tests for conditions associated with ASD as indicated by the initial clinical evaluation (see 'Evaluation for associated conditions' above)

●Diagnosis – The diagnosis of ASD is made clinically in children who meet established diagnostic criteria for ASD based on history and observation of behavior. There are two major sets of diagnostic criteria, both of which center on atypical social communication and interaction and restricted, repetitive patterns of behavior, activities, and interests:

•The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition Text Revision criteria for ASD (see 'Diagnostic criteria' above)

•The International Disease Classification 11th Revision criteria for ASD

●Additional evaluation – Additional evaluation may be necessary to identify comorbid conditions that have implications for treatment or genetic counseling. Additional evaluation usually includes genetic testing; other tests are individualized according to the history and clinical presentation. The yield of additional testing in the absence of clinical indications is low. (See 'Evaluation for associated conditions' above.)