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.

Adult advocates with ASD view autism as a personal characteristic that is a life-long part of an individual's identity and prefer identity-first (eg, "autistic individual") rather than person-first (eg, "individual with autism") language. They also prefer the term "autism" to "autism spectrum disorder." We respect these viewpoints. In this topic, we use "autism spectrum disorder (ASD)" and person-first language in agreement with the diagnostic terminology and the common style used in medical journals. However, clinicians should be sensitive to changes in terminology and inquire about individual preferences in discussions with their patients.

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 in children and adolescents: Screening tools".)

●(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 and prognosis".)

ROLE OF THE PRIMARY CARE CLINICIAN

●Surveillance for early identification – Primary care clinicians can identify children at risk for ASD through routine developmental, behavioral, and ASD-specific surveillance and screening using validated, standardized measures 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 (and/or increased or decreased responses to sensory experiences). (See 'Diagnostic criteria' below and "Autism spectrum disorder in children and adolescents: Clinical features", section on 'Terminology'.)

●Initiate evaluation for ASD and associated conditions – Although many children will need to see a specialist for a diagnostic evaluation, primary care clinicians and child psychologists comfortable with the application of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition Text Revision (DSM-5-TR) criteria for ASD can make an initial clinical diagnosis and evaluate for any comorbid or associated conditions. The primary care clinician can make a diagnosis of ASD using first- and second-tier screening instruments in conjunction with a comprehensive clinical evaluation if they have adequate clinical experience and training in the use of these tools. The comprehensive evaluation of ASD, including diagnostic and screening tools, are discussed in more detail elsewhere. (See 'Comprehensive evaluation' below and "Autism spectrum disorder in children and adolescents: Screening tools".)

A clinical diagnosis by the child's primary care clinician or child psychologist may facilitate insurance coverage for initiation of ASD specific services (eg, applied behavior analysis [ABA]) [1]. It is also often accepted by schools when determining the need for specialized instruction. However, while clinical criteria have significant overlap with educational criteria, they are not the same. In the United States, definitive diagnosis via the use of a diagnostic tool may be required for access to intensive behavioral interventions (eg, ABA) from the child's insurance plan. Thus, it is important to verify local educational system and insurance requirements for the given diagnosis to qualify the youth for treatment [2,3].

●Referral for definitive diagnosis – Children who are identified as being at risk for ASD through surveillance or screening whose primary care clinician is not certain of or require further confirmation of the diagnosis using a diagnostic tool 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 [4-6]. 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 [4,5,7-11].

●Referral for developmental and other interventions – Primary care clinicians who suspect that a child has ASD should refer the child for developmental-behavioral services, even if confirmation of the diagnosis by a specialist is pending. 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. In addition, the primary care clinician can initiate referrals for and counsel the family about ASD specific interventions and provide ongoing preventative care. (See "Autism spectrum disorder in children and adolescents: Overview of management and prognosis", section on 'Role of the primary care provider' and "Autism spectrum disorder in children and adolescents: Overview of management and prognosis", section on 'Treatment modalities'.)

The primary care clinician also can refer the child for supportive services (eg, autism navigator) (table 1) and recommend other interventions that the family can provide for the child while awaiting other services or specialist evaluation. The type of intervention varies depending on the parents'/caregivers' concerns and findings on developmental assessment [12]. Such interventions are not always specific to ASD but may support the family pending definitive diagnosis.

Examples of specific problems and interventions include:

•Difficulty with communication – Parents/caregivers can try using visual supports, avoiding the use of abstract terms (eg, metaphors, idioms), and providing concrete and explicit instructions when talking to the child.

•Atypical language – Parents/caregivers can use picture books to foster early reading, language comprehension, and expressive language skills. As importantly, books can be used to foster the development of social communication skills by building joint attention, awareness of people (including their feelings, thoughts, and beliefs), and the child's narrative and conversational skills. (See "Expressive language delay ("late talking") in young children", section on 'Prevention'.)

•Global developmental delay – Parents/caregivers can encourage language and cognitive development through social opportunities and language stimulation, as described in the preceding bullet.

•Difficulty with completing routine daily activities or transitioning between activities – Parents/caregivers can use a visual (eg, picture) schedule or social story to remind children what they need to do, when they need to do it, and when they can expect activities that they enjoy (eg, screen time). For example, picture schedules can be used to help children with limited language skills understand when tasks and routines have to be completed and when privileges are allowed. Social stories can be used to help children navigate novel or infrequent events, such as a trip to the doctor's office or traveling on an airplane. Examples of social stories are available online.

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

•Managing challenging behaviors – Children and youth with ASD often struggle with self-regulation and exhibit challenging behaviors (eg, hyperactivity, anxiety, aggression; sensory hypo- and hyper-responsiveness). The clinician can refer parents/caregivers to an evidence-based parent/caregiver training program, such as Triple P (Positive Parenting Programs), Parent-Child Interaction Therapy, or the Incredible Years [13]. These programs are first-line therapies that teach parents/caregivers about establishing a positive parent/caregiver-child relationship and healthy habits and behaviors (eg, good sleeping and eating habits, routines, and privileges). However, to be effective, they require parent/caregiver training and stricter adherence. Thus, more specialized interventions (eg, environmental modification and teaching self-regulation skills) may be needed to help children manage specific behaviors (eg, anger, anxiety). The clinician can help parents/caregivers identify and provide counseling on environmental modifications to manage these issues when possible. For example, using headphones may help to manage hyper-responsiveness by decreasing noise levels, and consistent schedules can help to manage anxiety by avoiding disruptions in routines.

•Coping with challenging behaviors – Parents/caregivers have differing abilities to tolerate challenging behaviors. The clinician can discuss the concept of temperament with them, administer a temperament scale (eg, one of the scales available from The Preventative Ounce [available with paid family membership]) to the child and parent/caregiver, and discuss "goodness of fit" (ie, a comparison of the child's temperament to the temperament of people in the child's environment) [14,15].

COMPREHENSIVE EVALUATION

Goals — The reference standard for evaluating a child for ASD consists of a comprehensive diagnostic assessment. Goals of the comprehensive diagnostic evaluation are to determine [4,5,10,16,17]:

●If the child's symptoms meet established diagnostic criteria for ASD. (See 'Diagnostic criteria' below.)

●The child's level of functioning and neurodevelopmental profile of strengths and weaknesses, which will affect the individualized management plan. (See 'Evaluation for associated conditions' below and 'Assessment of severity' below.)

●Whether the child has ASD, another condition (table 2 and table 3); or ASD and an associated condition such as intellectual or language impairments. (See 'Evaluation for associated conditions' below and 'Differential diagnosis' below.)

Evaluator(s) — A comprehensive assessment may be completed by an individual clinician (eg, primary care clinician, child psychologist, developmental-behavioral pediatrician) who has expertise in the diagnosis and management of ASD or by a multidisciplinary team with a lead clinician who has this expertise. The multidisciplinary team may include a developmental-behavioral pediatrician, child psychiatrist, child neurologist, or (neuro)psychologist, a speech and language pathologist, and an educator [4-11,16]. Each team member 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.

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

Important aspects of the history include [4,10,19]:

●Early ASD symptoms (children <5 years of age) – In younger children, it is important to review the developmental history, with special attention to early social-emotional and language milestones, play skills and behaviors, and loss of skills (table 4 and table 5). It is particularly useful to ask about:

•Impaired social communication and interaction, such as:

-Absent or limited interest in playing with other children, or limited imaginary play (eg, mimicking social activities or events as part of pretend play with dolls or stuffed animals).

-Absent or limited responsiveness when called by name, shared enjoyment with parent/caregiver, use of eye contact during communication, and use of pointing as a means of communication.

•Repetitive behaviors/restricted interests and atypical sensory reactions, such as:

-Flapping, spinning, twirling, or being overly focused on specific types of play activities (eg, trains, cars, or other mechanical interests), often with a marked exclusion of other age-appropriate activities.

-Increased or decreased reactions to sensory experiences (eg, sensitivity to noise or texture, restricted diet, seeking sensory input).

●ASD symptoms in school-aged children and adolescents – ASD symptoms in older children vary with the child's developmental level at the time of presentation. Older children with ASD commonly struggle with taking turns in a play interaction or conversation, show limited nonverbal communication skills (eg, eye contact or changes in facial expressions, gestures, and intonation), and have difficulty understanding expressions or metaphors (eg, "it's raining cats and dogs") (table 5).

ASD symptoms may also vary by gender. For example, girls with ASD may present with less severe symptoms (eg, ritualized behaviors and social functioning), which may present diagnostic challenges, as discussed below. (See 'Effect of gender on diagnosis' below.)

It is useful to elicit specific information about:

•Social and communication behaviors, such as:

-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 peers or adults? Are interaction attempts designed to only satisfy the child's wants and needs or do they also imply an interest in social interaction?

-Capacity to socialize successfully by using appropriate communication and interaction behaviors: Does the child make social bids to peers or adults, and are they able to respond to the social bids of others? Are the social bids typical or atypical? For example, a typical social bid might be to say 'hi' or to ask a question. An atypical social bid might be to get too close to the conversational partner, or to push or touch the conversational partner in an inappropriate manner.

-Development of peer relationships and friendships: Is the child able to develop age-appropriate peer relationships and to maintain friendships? Is the child able to make the distinction between who is a friend versus who is an acquaintance or a stranger?

-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 do they also occur when looking at pictures or reading books?

-Capacity for self-awareness and perspective-taking: Does the child have insight into social and behavioral problems and their role in relationships?

•Ritualized behaviors and atypical sensory reactions, such as:

-Repetitive/stereotyped behaviors (eg, hand-flapping, spinning self or objects, rocking behaviors, echolalia).

-Insistence on sameness or inflexible behavior (eg, picky eating such as eating particular foods in a specific order); difficulty tolerating transitions or changes in routines; frequent tantrums.

-Very specific or mechanical interests (eg, trains, subway lines, vacuum cleaners, ceiling fans, sports scores, types of nail polish).

-Increased or decreased response to sensory stimuli and unusual visual behavior (eg, staring at objects, preoccupation with parts of toys).

●Associated symptoms and conditions – For example:

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

•Self-injury

•Seizures

•Depression (in adolescents and adults)

•Anxiety

•Language and learning difficulties

•Challenges with attention

●Family history – ASD has a strong genetic component. 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 [4,10]. These include:

•Neurological and developmental conditions, such as:

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

-Intellectual disability

-Language delay/disorders

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

-Tic disorders

-Seizures

•Behavioral and psychiatric conditions, such as:

-Anxiety and mood disorders

-Extreme shyness, social phobia, or selective mutism

-Obsessive-compulsive disorder

-Schizophrenia

•Specific syndromes, such as:

-Tuberous sclerosis complex

-Fragile X syndrome

-Rett syndrome

-Angelman syndrome

-Prader-Willi syndrome

-Smith-Lemli-Opitz syndrome

Conditions associated with ASD and the pathophysiology of ASD are discussed in more detail elsewhere. (See 'Differential diagnosis' below and "Autism spectrum disorder (ASD) in children and adolescents: Terminology, epidemiology, and pathogenesis".)

●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 a different treatment approach [20]. (See 'Differential diagnosis' below.)

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

Important aspects of the physical examination include [4]:

●Weight – Restricted dietary patterns can result in poor weight gain, obesity, or other nutritional problems. (See "Autism spectrum disorder in children and adolescents: Clinical features", section on 'Feeding problems'.)

●Head circumference – Assessment of head circumference (OFC) includes measurement of OFC size and growth trajectory (if previous measurements are available). Children with ASD often have early acceleration of head growth, followed by stabilization [21]. Isolated macrocephaly can occur in one-fourth of children with ASD, but may also be associated with pathogenic genetic variants [22,23]. Microcephaly occurs in approximately 15 percent of children with ASD and is usually associated with other conditions (eg, Angelman syndrome, Smith-Lemli-Opitz syndrome) [24].

These conditions are discussed in more detail elsewhere. (See "Autism spectrum disorder in children and adolescents: Clinical features", section on 'Macrocephaly' and "PTEN hamartoma tumor syndromes, including Cowden syndrome", section on 'Autism spectrum disorders and macrocephaly' and "Microcephaly in infants and children: Etiology and evaluation".)

●Neurological findings – Examination of muscle tone and reflexes may reveal motor deficits such as mild hypotonia or neurodevelopmental findings that occur in syndromes with ASD. Focal neurologic findings, such as asymmetry in tone or reflexes, require further neurologic evaluation and possibly neuroimaging. (See 'Other testing' below and "Autism spectrum disorder in children and adolescents: Clinical features", section on 'Motor deficits'.)

●Other findings – Examination may reveal dysmorphic features or other findings of genetic syndromes associated with ASD (table 3). Examination with a Wood lamp may be helpful in demonstrating the hypopigmented macules of tuberous sclerosis complex (picture 1). (See "Autism spectrum disorder (ASD) in children and adolescents: Terminology, epidemiology, and pathogenesis", section on 'Associated conditions and syndromes' and "Tuberous sclerosis complex: Clinical features".)

Diagnostic tools — Diagnostic tools for ASD are used to gather behavioral data in a structured and consistent manner, either through an interview with the parents/caregivers or, more commonly, by making direct observations of the child. Most require intensive training to administer and are generally administered by a specialist but can be administered by a primary care clinician with experience and training. Diagnostic tools are used in conjunction with clinical judgment to make a diagnosis of ASD; they should not be used in isolation [4,5]. In the United States, the use of a diagnostic tool may be required for access to intensive behavioral interventions (eg, Applied Behavior Analysis) from the child's insurance plan.

●Choosing a tool – A number of diagnostic tools (table 6) are available but their accuracy has not been well studied [17,25]. 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 [26,27]. These and the other tools listed below are recommended in national guidelines [4,9-11]. Other diagnostic instruments and rating scales are less sensitive and specific [17,25,28]. The TELE-ASD-PEDS is under investigation as a diagnostic tool for children under 36 months of age that can be used during telehealth visits to assess for ASD symptoms by observing the child during interactions with the parent/caregiver [29,30]. We recommend not using The Gilliam Autism Rating Scale (GARS) as a diagnostic tool. Although it can be used as a screening instrument, it has poor diagnostic validity (ie, underdiagnosis of ASD) and inter-rater reliability [31,32].

Recommended tools include:

•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 [33].

•Childhood Autism Rating Scale-2^nd edition (CARS-2) – The CARS-2 may be suitable for use by a primary care clinician when paired with direct, structured observation of the child to evaluate joint attention, social-emotional reciprocity, and other symptoms.

•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.

A systematic review of observational studies evaluating diagnostic accuracy in children <6 years of age who underwent multidisciplinary evaluation for ASD (the reference standard) found no studies evaluating GARS, 3di, or DISCO that met inclusion criteria [17]. The studies evaluating ADI-R, CARS, and ADOS showed substantial variation in sensitivity and specificity, likely related to differences in study populations and methodology. There were too few studies to permit meaningful direct comparisons among these tools; however, summary statistics for each tool revealed that ADOS was most sensitive (94 percent compared with 80 percent for CARS and 52 percent for ADI-R), and 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. A study comparing the use of a formal diagnostic tool versus clinical judgment alone showed that among developmental-behavioral pediatricians, clinical diagnoses of ASD by clinicians with versus without the ADOS were consistent in 90 percent of cases [34]. These findings support the role of experienced clinical judgment in any diagnostic evaluation.

●Digital tools – Digital tools incorporating eye-tracking measures have been studied as potential biomarkers to objectively assess for ASD risk and symptoms of social disengagement/inattention [35,36]. In a cohort study of 146 children (age 14 to 48 months), eye-tracking indices in combination with diagnosis by the primary care clinician were concordant with the diagnostic reference standard (ie, diagnosis made by specialist) for 114 of 127 (90 percent) of cases, with a sensitivity of 90.7 percent (95% CI, 83.3-95.0) and a specificity of 86.7 percent (95% CI, 70.3-94.7) [36]. Although these tools show promise and are now commercially available, additional evaluation is needed for application to clinical practice.

Evaluation for associated conditions — Evaluation for associated conditions generally includes assessment for co-occurring developmental and functional impairment, genetic and lead testing. Other tests (eg, metabolic or neuroimaging) are individualized according to the history and clinical presentation [4,10], but the yield in the absence of clinical indications is low [37].

Additional evaluation is necessary to:

●Corroborate and confirm the diagnosis of ASD (see 'Diagnosis' below)

●Determine the child's level of impairment and identify targets for therapeutic intervention

●Differentiate ASD from other conditions that mimic ASD (table 2) (see 'Differential diagnosis' below)

●Identify conditions that co-occur with ASD, including comorbid conditions that require specific treatment or genetic counseling (table 3) [7,9]

Developmental/functional assessment — Evaluation for co-occurring developmental and functional impairment includes [4,7,10,19]:

●Speech and language assessment – The speech and language assessment is typically performed by a speech and language pathologist. It 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 and "Speech and language impairment in children: Evaluation, treatment, and prognosis".)

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

•Formal language functions (eg, phonological awareness and articulation, vocabulary, grammar, syntax, and narrative).

•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 one to one testing situation where there is usually more time to review, reflect upon, and respond to social information. They may not perform as well in real-time situations (eg, classroom discussion, peer interaction), where information-gathering and social responsiveness need to occur more rapidly.

●Developmental/intelligence testing – Developmental/intelligence testing provides additional information on developmental and cognitive abilities and should include 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. (See "Intellectual disability (ID) in children: Clinical features, evaluation, and diagnosis", section on 'Diagnosis' and "Specific learning disorders in children: Role of the primary care provider".)

●Adaptive skills assessment – Adaptive skills assessment provides information on the individual's ability to function in different settings (eg, social interaction/communication, problem-solving, independent living skills). It helps to document findings associated with intellectual disability and 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 – Assessment of sensorimotor function helps to evaluate the type and extent of sensory hypo- or hyper-responsiveness and to provide therapy for fine motor coordination problems.

●Vision and hearing assessment – If not already performed, vision and hearing should be assessed to evaluate for any deficits, as these can be associated with developmental impairment [4]. (See "Vision screening and assessment in infants and children" and "Hearing loss in children: Screening and evaluation".)

Genetic testing — Our approach to genetic testing of children with ASD is consistent with recommendations of the American College of Medical Genetics and Genomics and the International Standards for Cytogenomic Arrays Consortium [37-42]:

●Initial genetic tests – Genetic testing should be performed by a clinician who is familiar with the range of testing options available and who can provide psychoeducational counseling to patients and families to help them understand the results. Consultation with or referral to a clinical geneticist may be helpful 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).

Standard testing includes chromosomal microarray (CMA) and deoxyribonucleic acid (DNA) analysis for fragile X, whether or not the child has dysmorphic features. Consultation with a clinical geneticist 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. Karyotype is warranted if a balanced translocation is suspected (eg, history of ≥2 miscarriages) because CMA does not detect balanced translocations [37]. However, truly balanced de novo translocations are rare [43]. (See "Tools for genetics and genomics: Cytogenetics and molecular genetics" and "Next-generation DNA sequencing (NGS): Principles and clinical applications".)

Potential benefits of identifying a genetic diagnosis include:

•Prevention of associated medical complications for the child.

•Prevention of further search for complementary and alternative diagnoses and treatments, which are often nonevidence based and expensive.

•Provision of specific information about recurrence risk for family members.

•Provision of emotional relief for the parents/caregivers, which 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 genetic testing affects health outcomes [44]. In addition, a recognizable disorder is found in a minority of cases, usually in patients with comorbid global developmental delay or intellectual disability, or more severe dysmorphology. 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 CMA (ie, array comparative genomic hybridization) identified abnormal deletions or duplications in 7 percent [45].

Although CMA has the highest detection rate among clinically available genetic tests for patients with ASD, it is less sensitive than exome and genome sequencing [45-48]. In a meta-analysis of 30 studies, exome sequencing was reported to have an overall diagnostic yield of 36 percent for unexplained neurodevelopmental disorders (eg, global developmental delay, intellectual disability, and/or ASD) compared with a 15 to 21 percent yield for CMA based on previous studies [47]. The diagnostic yield of exome sequencing for isolated disorders was 31 percent and increased to 53 percent when associated neurodevelopmental conditions were present.

In a population-based study included in the above analysis, CMA yielded a molecular diagnosis in 9.3 percent of 258 unrelated children who were diagnosed with ASD [48]. Among the 95 children who underwent both CMA and whole-exome sequencing, the yield of exome sequencing was similar to that of CMA (8.4 percent), and the combined yield of CMA and exome sequencing was 15.8 percent. Molecular diagnosis was achieved more often in children with more severe dysmorphology. Although these findings suggest that exome sequencing should be considered as a first-line diagnostic test in children with neurodevelopmental conditions such as ASD, molecular diagnosis appears to be most useful in identifying children with the greatest likelihood of genetic diagnosis [47,49]. Moreover, exome and genome sequencing may be costly and not covered by all insurance carriers.  

●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 [38,50]. 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 variant may be warranted for patients, particularly females, with a history of acquired microcephaly and significant developmental regression [51,52]. (See "Rett syndrome: Genetics, clinical features, and diagnosis".)

•Testing for pathogenic variants 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) [38]. (See "PTEN hamartoma tumor syndromes, including Cowden syndrome", section on 'Autism spectrum disorders and macrocephaly'.)

Other testing

●Lead testing – If not already performed, lead testing is warranted to evaluate for lead poisoning, which is a potential cause of developmental and behavioral problems and is associated with pica in children with ASD or intellectual disability [4]. (See "Childhood lead poisoning: Clinical manifestations and diagnosis".)

●Metabolic testing – Metabolic testing is rarely warranted in children with ASD but may be indicated in those with symptoms or signs of a metabolic disorder, including [51,53-55]:

•Physical findings such as:

-Dysmorphic or coarse features

-Failure to thrive

-Macrocephaly

-Hepatosplenomegaly

-Unusual odors

-Vision impairment

-Hearing impairment

•Neurological or developmental findings such as:

-Lethargy or limited endurance (particularly if associated with mild illness)

-Hypotonia or hypertonia

-Ataxia

-Dyskinesis

-Nystagmus

-Early seizure

-Intellectual disability (suspected or confirmed)

-Developmental regression

•Other findings such as:

-Inadequate or questionably adequate newborn screen

-Recurrent vomiting and dehydration

-Specific food intolerance (eg, protein)

The evaluation is individualized according to the clinical features. Consultation with a clinical geneticist is suggested. Additional testing may also be indicated to evaluate for other conditions that may present with similar symptoms (eg, intellectual disability, epilepsy, gastrointestinal disorders). Disorders of amino acid, carbohydrate, purine, peptide, and mitochondrial metabolism account for <5 percent of cases of ASD [51,54]. In observational studies, in the absence of signs or symptoms of metabolic disease, metabolic testing has low yield [38,53,56,57].

The clinical features, evaluation and management of metabolic and other disorders are discussed in more detail separately. (See "Inborn errors of metabolism: Epidemiology, pathogenesis, and clinical features" and "Intellectual disability (ID) in children: Evaluation for a cause" and "Approach to the infant or child with nausea and vomiting".)

●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 was low in children with ASD and no other neurologic findings (eg, intellectual disability, abnormal neurologic examination, seizures, headache, focal neurologic findings) [53,58].

●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 [4,51]. Among children with ASD and staring spells, EEG rarely yields clinically significant findings [59] and thus is not routinely recommended. (See 'Differential diagnosis' below and "Epilepsy syndromes in children", section on 'Developmental and epileptic encephalopathies with spike-wave activation in sleep'.)

Tests that are not indicated — The following tests are not indicated, as no empiric data support such analyses [51]:

●Yeast metabolites

●Gut permeability

●Heavy metals (other than lead)

●Trace elements or micronutrients

●Immune abnormalities

DIAGNOSIS

Diagnostic criteria — The diagnosis of ASD is made clinically in children who meet established diagnostic criteria for ASD as identified by both history and observation of behavior. The terminology and diagnostic criteria for ASD are based on The Diagnostic and Statistical Manual of Mental Disorders, Fifth edition Text Revision (DSM-5-TR), which is used in the United States, and the ICD-11 (World Health Organization) [60-62].

●DSM, Fifth edition Text Revision (DSM-5-TR) criteria – Two major symptom clusters make up the DSM-5-TR diagnostic criteria. Cluster "A" symptoms are focused on impairments in social communication and social interaction behaviors in multiple settings. Cluster "B" symptoms are focused on repetitive patterns of behavior, restricted activities and interests, and atypical sensory behaviors and experiences. (See 'History' above.)

According to the DSM-5-TR criteria, a diagnosis of ASD requires all of the criteria, as listed below, based on current or prior history [61].  

•All three of the following cluster A symptoms:

-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 such as eye contact, facial expressions, gestures, body language, and/or prosody/tone of voice)

-Difficulty developing, understanding, and maintaining 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)

•Two or more of the following cluster B symptoms:

-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 such as 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)

•And the symptoms:

-Significantly impair social, academic/occupational, and daily function, and

-Are not better explained by intellectual disability or global developmental delay, and

-Are present in early childhood (However, symptoms may become apparent only after social demands exceed the child's limited capacity; in later life, they may be masked by learned strategies.)

The presence or absence of co-occurring medical, genetic, neurological, neurodevelopmental, psychiatric, or behavioral conditions are specified as part of the DSM-5-TR diagnosis of ASD (eg, ASD with accompanying intellectual impairment, ASD without accompanying language impairment) [61]. These conditions can be identified during the comprehensive evaluation, and some (eg, genetic or metabolic conditions) may require additional diagnostic testing. (See 'Comprehensive evaluation' above and 'Differential diagnosis' 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 [62].

The ICD-11 diagnostic criteria for ASD are similar to those of the DSM-5-TR, as they require similar essential features and also specify the presence or absence of co-occurring intellectual disability and the degree of functional language impairment.

Assessment of severity — In conjunction with an adaptive behavior rating scale (eg, Vineland Adaptive Behavior Scale, Adaptive Behavior Assessment System), the DSM-5-TR includes a classification system to indicate the level (ie, 1, 2, or 3) of ASD severity and support required by the child. The severity of impairment and associated level of support should be assessed separately for each domain. Severity may vary with context and over time [61]. Co-occurring intellectual impairment often accounts for the differences in severity.

●Social communication/social 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 behaviors/restricted interests

•Level 1 ("Requiring support") – Behaviors significantly interfere with function; difficulty switching between activities; difficulty understanding that activities and the daily schedule occur in a predictable pattern (first-then; or, first-next-next- after that- last).

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 [63].

•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)

Effect of gender on diagnosis — More boys than girls are diagnosed as having ASD. The diagnostic ratio is approximately 3 to 1 [64]. Girls who meet the criteria for ASD are at disproportionate risk of not receiving a clinical diagnosis. In particular, girls with ASD who have typical intelligence may be at risk for a delay in diagnosis [65]. (See "Autism spectrum disorder (ASD) in children and adolescents: Terminology, epidemiology, and pathogenesis", section on 'Male-to-female ratio'.)

The underdiagnosis in girls may be due to true neurodevelopmental differences between boys and girls or to different clinical presentations and the "masking" of symptoms, which is potentially higher in girls [65-68]. Clinically, girls with ASD appear to exhibit less severe symptoms of repetitive and stereotyped behaviors than boys [65,66]. Although there are reportedly no differences in their social behaviors or communication skills, girls with ASD may be socially more motivated than boys. They may have better imaginative play, show more interest in social relations, and may have more socially acceptable interests (eg, repetitive hair twirling), which might mask ASD symptoms [65-67]. Children with intellectual disability can have restricted interests and behaviors. As such, girls identified as having ASD may disproportionately have a coexistent intellectual disability [65].

Diagnostic stability — Accurate diagnosis depends upon the information-gathering procedures described above. Accurate diagnosis also requires confirmation of the diagnosis over time (known as "diagnostic stability"). Although the majority of children continue to meet the criteria for ASD as they age, a significant proportion of children diagnosed as having ASD in the toddler years may no longer meet these criteria over time. This trajectory is important to recognize for effective treatment planning and when discussing long-term outlook with the family.

Diagnostic stability appears to increase with increasing age at the time of initial diagnosis when using criteria in the DSM-5 and DSM IV (or earlier versions) [69-73]. ASD has high diagnostic stability when the diagnosis is made at ≥24 months. In a systematic review of screening studies, the diagnostic stability of ASD ranged from 68 to 100 percent [74]. However, diagnostic stability appears to be present as early as age 14 months [75].

In a meta-analysis of 23 randomized trials and nonrandomized studies including a total of 1466 participants (mean duration of follow-up between 2.1 and 32.5 years), the overall diagnostic stability of ASD was 85 to 89 percent; however, it varied depending on the age of diagnosis and increased with higher age at diagnosis [69]. For example, up to 30 percent of children who were diagnosed before three years of age no longer met criteria for ASD at follow-up, in comparison with up to 20 percent of those diagnosed between three to five years of age and up to 16 percent of those diagnosed after five years of age. In a subsequent cohort study, 37 percent of children who were diagnosed with ASD before three years of age no longer met criteria for ASD at five to seven years of age [73]. Based on these findings, clinicians should counsel families that the newly diagnosed child with ASD may not meet criteria for an ASD after a period of follow-up, particularly if initial diagnosis occurred during the preschool years in children.

DIFFERENTIAL DIAGNOSIS

Overview — The differential diagnosis of ASD includes a number of conditions that impair social communication or social interaction and/or are associated with restricted or stereotypic movements (table 2) [4,8,10]. 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 [61,76-78]. An important function of the comprehensive evaluation is to determine whether the child has ASD, another condition, or ASD and a co-occurring condition. ASD can be distinguished from conditions in the differential diagnosis by a history of reduced or inconsistent social reciprocity. However, impairment in social reciprocity and other symptoms must be best explained by ASD and not by the co-occurring condition. (See 'Goals' above and 'Diagnostic criteria' above.)

However, 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 ASD from situations where the child or adolescent has a dual diagnosis, such as attention deficit hyperactivity disorder (ADHD) and anxiety; ADHD and a language impairment, or social anxiety disorder and language impairment. These dual diagnosis situations can mimic ASD. They can be especially difficult to separate from ASD in children with average or superior intelligence.

Conditions in the differential diagnosis of ASD in children, and which mimic or lack the core features of ASD, are discussed below [4,8,10].

Other conditions with atypical social interaction

●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 [79]. In addition, intellectual disability is common among children with ASD [80,81]. (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 [10]. Clinical features that are more characteristic of ASD than isolated global developmental delay/intellectual disability include impaired nonverbal behaviors and lack of social/emotional reciprocity [82].

●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. This includes difficulty taking turns in a conversation, producing on-topic (contingent) responses, maintaining a mutually agreed-upon conversational topic, producing a narrative that meets the listener's needs, recognizing and addressing conversational breakdowns; and failure to recognize nonliteral or ambiguous meanings of language (eg, idioms, humor) [83]. Social communication disorder is distinguished from ASD by the absence of restricted, repetitive patterns of behavior, interests, or activities.

●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'.)

●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 parent/caregiver [84]. In addition, the social deficits of children with attachment disorder tend to improve in response to an appropriate caregiving environment.

●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 unaffected. In contrast with ASD, children with LKS do not exhibit restricted, repetitive patterns of behavior or interests. (See "Epilepsy syndromes in children", section on 'Developmental and epileptic encephalopathies with spike-wave activation in sleep'.)

Other conditions with repetitive/restricted behaviors

●Obsessive-compulsive disorder – Obsessive-compulsive disorder (OCD) has behavioral features (eg, repetitive behaviors) 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 [85]. However, children with ASD may have symptoms of OCD that they find distressing. Children with OCD usually have typical 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 motor behaviors (eg, hand flapping, head banging) that may result in self-injury [86,87]. However, unlike children with ASD, children with stereotypic movement disorder usually have typical 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 typical 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'.)

●Rett syndrome – Rett syndrome is a neurodevelopmental disorder that occurs almost exclusively in females. 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. 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. (See "Rett syndrome: Genetics, clinical features, and diagnosis", section on 'Classification and major features'.)

Other conditions with ASD features but without atypical social interaction or repetitive/restricted behaviors

●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 typical pragmatic language skills, and can explain their intense interests, which are functional and varied. (See "Children who are gifted: Characteristics and identification".)

●Language disorder/Language-based learning disorder – In contrast to children with ASD, children with developmental language disorders or language-based learning disorders have typical reciprocal social interactions, desire and intent to communicate, and appropriate imaginative play [10,88]. 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 "Speech and language impairment in children: Etiology", section on 'Language disorders' and "Specific learning disorders in children: Clinical features", section on 'Language-based learning disorder'.)

●Hearing loss – In contrast to children with ASD, children with hearing loss usually have typical reciprocal social interactions, imaginative play, eye-to-eye gaze, and facial expressions indicative of their intention to communicate [88].

●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. 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. In contrast to children with ASD, children with primary anxiety disorders usually have typical nonverbal social behavior and imaginary play [89]. 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. (See "Anxiety disorders in children and adolescents: Epidemiology, pathogenesis, clinical manifestations, and course" and "Anxiety disorders in children and adolescents: Assessment and diagnosis".)

●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 typical pragmatic language skills, nonverbal social behavior, and imaginary play [89,90]. (See "Attention deficit hyperactivity disorder in children and adolescents: Clinical features and diagnosis", section on 'Clinical features'.)

FOLLOW-UP — 

Follow-up with the primary care clinician is recommended within one to six months of initial diagnosis to address behavioral, environmental, and other developmental concerns with guidance from specialists as needed [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. In particular, reassessment of social skills provides an important measure of responsiveness to therapies and diagnostic stability. Follow-up 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.

The primary care clinician should continue to see the patient every 6 to 12 months; however, more frequent follow-up may be needed for children receiving pharmacotherapy or who have other conditions (eg, anxiety, sleep disturbance, aggressive behaviors) that require closer monitoring. Long-term support is critical for children with ASD and their families and should include transition planning for adolescence and adulthood [4]. Siblings of children with ASD should also be monitored for symptoms of ASD and associated conditions [4]. Treatment with pharmacotherapy, family support, transition planning, and familial recurrence in siblings of children with ASD are discussed in more detail separately. (See "Autism spectrum disorder in children and adolescents: Pharmacologic interventions" and "Autism spectrum disorder in children and adolescents: Overview of management and prognosis", section on 'Family support' and "Autism spectrum disorder in children and adolescents: Behavioral and educational interventions", section on 'Transition planning' and "Autism spectrum disorder (ASD) in children and adolescents: Terminology, epidemiology, and pathogenesis", section on 'Rate in siblings'.)

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 and other discussions are available in the table (table 1).

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 clinician – Primary care clinicians can (see 'Role of the primary care clinician' above):

•Identify children at risk for ASD.

•Initiate evaluation for ASD and associated conditions. While an experienced primary care clinician can make the diagnosis, referral to a specialist for comprehensive evaluation may be needed to confirm the diagnosis and/or to evaluate for comorbid conditions.

•Refer for developmental and behavioral interventions and supportive services (table 1).

•Suggest interventions that the family can provide while awaiting other services or specialist evaluation.

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

•If the child's symptoms meet established diagnostic criteria for ASD. (See 'Diagnostic criteria' above.)

•The child's level of function and neurodevelopmental profile of strengths and weaknesses. (See 'Evaluation for associated conditions' above and 'Assessment of severity' above.)

•Whether the child has ASD, another condition (table 2 and table 3); or ASD and an associated condition such as intellectual or language impairments. (See 'Evaluation for associated conditions' above and 'Differential diagnosis' above.)

●Components of comprehensive evaluation

•History – The history is usually obtained from the parents/caregivers, but teachers, therapists, and other professionals also can provide useful information. It focuses on (see 'History' above):

-Current ASD symptoms and those presenting in early childhood (table 4 and table 5)

-Other associated symptoms or conditions

-Family history of ASD, associated conditions, or conditions with similar symptoms

-Psychosocial history

•Physical examination – The physical examination includes assessing the consequences of restricted, repetitive dietary patterns and signs of associated conditions (eg, abnormalities in weight or head circumference, neurologic or neurocutaneous findings, or dysmorphic features). (See 'Examination' above.)

•Diagnostic tools – Diagnostic tools (table 6) 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 are generally administered by a specialist but can be administered by a primary care clinician with adequate clinical experience and training. (See 'Diagnostic tools' above.)

•Evaluation for associated conditions – Evaluation for associated conditions is warranted to confirm the diagnosis of ASD, to differentiate ASD from conditions that may mimic or co-occur with ASD (table 2 and table 3), and to determine the child's level of impairment and identify targets for therapeutic intervention. Evaluation includes assessment for co-occurring developmental and functional impairment, and genetic and lead testing. Other tests (eg, metabolic or neuroimaging) are individualized according to the history and clinical presentation. (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 and interests, including atypical sensory behaviors (see 'Diagnostic criteria' above):

•The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition Text Revision (DSM-5-TR) criteria for ASD

•The International Disease Classification 11th Revision criteria for ASD

The severity of impairment and associated level of support should be assessed separately for each domain. ASD is underdiagnosed in girls. Diagnostic stability varies depending on age at the time of initial diagnosis. (See 'Diagnosis' above.)

●Differential diagnosis – The differential diagnosis of ASD includes conditions that impair social communication or social interaction and/or are associated with restricted or stereotypic movements (table 2). These conditions can co-occur with ASD or may be the cause of ASD-like symptoms in a child without ASD. ASD can be distinguished from these conditions by a history of reduced or inconsistent social reciprocity, but impairments must be best explained by ASD and not by the co-occurring condition. (See 'Differential diagnosis' above.)

●Follow-up – Follow-up is recommended within one to six months of initial diagnosis to address behavioral, environmental, and other developmental concerns. In addition, the primary care clinician should continue to see the patient every 6 to 12 months; however, more frequent follow-up may be needed for children receiving pharmacotherapy or who have other conditions (eg, anxiety, sleep disturbance, aggressive behaviors) that require closer monitoring. Siblings of children with ASD should also be monitored for symptoms of ASD and associated conditions. (See 'Follow-up' above.)