Autism spectrum disorder in children and adolescents: Terminology, epidemiology, and pathogenesis

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 terminology, epidemiology, and pathogenesis of ASD will be reviewed here. Surveillance and screening, clinical features, diagnosis, 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: Clinical features".)

●(See "Autism spectrum disorder in children and adolescents: Evaluation and diagnosis".)

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

TERMINOLOGY — The terminology and diagnostic criteria for ASD vary geographically.

●The Diagnostic and Statistical Manual of Mental Disorders (DSM) is used predominantly in the United States and was updated in 2022 (DSM-5-Text Revision [DSM-5-TR]) [1].

●The World Health Organization International Classification of Diseases, 11th Revision (ICD-11) is used in other countries throughout the world [2]. The 11^th revision was implemented in 2022.

With the 2022 implementation, ICD-11 changed the terminology for ASD to be consistent with that in DSM-5 and DSM-5-TR [2,3]. ASD is the "parent" term and is further characterized by the presence or absence of a disorder of intellectual development and/or impairment or absence of functional language. In ICD-10, ASD was classified as a "pervasive developmental disorder" with several subtypes (eg, childhood autism, atypical autism, and Asperger syndrome).

In both systems, ASD is characterized by [1,4]:

●Persistent deficits in social communication and reciprocal social interaction (eg, deficits in social reciprocity; nonverbal communicative behaviors; and skills in developing, maintaining, and understanding relationships), and

●Restricted, repetitive, and inflexible patterns of behavior, interests, or activities

The symptoms must be present in early development. However, because symptoms may not be apparent until social demands exceed limited capacities, no age threshold for "early development" is specified. The symptoms also must substantially impair functioning in personal, social, educational, occupational, or other important areas.

The diagnosis of ASD is qualified by a number of specifiers, including the presence or absence of associated conditions (eg, intellectual impairment, language impairment). The DSM-5-TR also includes qualifiers for three levels of severity, which are rated separately for social communication and restricted, repetitive behaviors) [1].

The diagnostic criteria for ASD are similar, but not identical, in DSM-5-TR and ICD-11 [3]. They are discussed separately. (See "Autism spectrum disorder in children and adolescents: Evaluation and diagnosis", section on 'Diagnostic criteria'.)

EPIDEMIOLOGY

Prevalence — Estimates of the prevalence of ASD vary with study methodology and the population that is evaluated. The overall prevalence of ASD in Europe, Asia, and the United States ranges from 2 to 25 per 1000, or approximately 1 in 40 to 1 in 500 [5-20].

Three national databases are used to estimate ASD prevalence in the United States:

●The Autism and Developmental Disabilities Monitoring (ADDM) Network identifies ASD through screening and abstraction of existing health and education records among eight-year-old children at selected study sites. For 2020, the surveillance case definition included any of the following: an ASD diagnostic statement in an evaluation, a classification of ASD in special education, or an ASD International Classification of Diseases code [20].

In 2020, the estimated prevalence was 27.6 per 1000 (1 in 36) eight-year-old children overall, 1 in 23 males, and 1 in 88 females [20]. The prevalence estimates varied from 23.1 to 29.8 per 1000 children between sites, except for California, where the prevalence was 44.9 per 1000. Compared with prior years, 2020 was the first year that prevalence was lower in White children (24.3 per 1000) than in all other racial and ethnic groups.

●The Early ADDM Network identifies ASD through screening and abstraction of existing health and education records among four-year old and eight-year old children at selected study sites. The Early ADDM Network uses similar case definitions as the ADDM Network described above.

In 2020, the estimated prevalence was 21.5 per 1000 (1 in 47) four-year-old children overall, 1 in 31 males, and 1 in 96 females [21]. Prevalence estimates varied widely by site and by race/ethnicity (16.3 per 1000 among non-Hispanic White children, 25.3 per 1000 non-Hispanic Black children, 28.7 per 1000 among Hispanic children, and 23.5 among Asian/Pacific Islander children). Evaluations for autism decreased during the coronavirus disease 2019 (COVID-19) pandemic. Screening levels recovered but had not returned to baseline by the end of this surveillance period.

●The National Health Interview Survey (NHIS) estimates the prevalence of ASD in children age 3 through 17 years according to parent report of a clinician diagnosis [15]. In the 2016 NHIS, the estimated prevalence of ASD was 25 per 1000 (95% CI 22.3-28.1 per 1000): approximately 1 in 40 children overall, 1 in 26 males, and 1 in 93 females.

The prevalence of ASD has increased over time, particularly since the late 1990s [22-24]. Systematic reviews of epidemiologic studies suggest that changes in case definition and increased awareness account for much of the apparent increase [22,25-28]. Other factors that may play a role include earlier detection, availability of more specialized developmental services, diagnostic substitution (ie, increases in prevalence of ASD accompanied by decreases in the prevalence of learning disorders, developmental language disorder, and/or intellectual disability [ID]), as well as a true increase in prevalence [10,25,27,29-35].

Male-to-female ratio — ASD is three to four times more common in males than females [17,24,36,37]. In a systematic review of 54 studies including >13,700,000 patients, the overall male-to-female ratio was 4.2 (95% CI 3.8-4.6) [36]. However, in higher-quality studies and in studies that screened the general population for cases of ASD, the male-to-female ratio was closer to 3, suggesting that ASD may be underdiagnosed in females.

Rate in siblings — The estimated prevalence of ASD in siblings of a child with ASD who does not have an associated medical condition or syndrome is approximately 10 percent (range 4 to 14 percent) [38-41]. However, in some studies, the prevalence of ASD in siblings of children with ASD is as high as 20 percent [38,42,43].

Younger male siblings of a child with ASD are more often affected than younger female siblings, but the risk of recurrence appears to be increased when the index patient is a female. An administrative database study evaluated the recurrence of ASD among children in >1.5 million families with two children age 4 to 18 years between 2008 and 2016 [43]. The overall prevalence of ASD was 1.25 percent. Among the families in which the older child had ASD, the risk of recurrence varied as follows according to the sex of the siblings:

●Younger brothers of females with ASD – 17 percent

●Younger brothers of males with ASD – 13 percent

●Younger sisters of females with ASD – 8 percent

●Younger sisters of males with ASD – 4 percent

The 2013 American College of Medical Genetics and Genomics practice guideline provides the following risks for ASD in siblings of children with ASD without an identifiable etiology: 7 percent if the affected child is female, 4 percent if the affected child is male, and ≥30 percent if there are two or more affected children [38,44,45].

Siblings of children with ASD may have symptoms of ASD even if they do not meet criteria for diagnosis of ASD (sometimes called the "broad ASD phenotype"). In observational studies, symptoms of ASD or associated neurodevelopmental abnormalities were more common among siblings of ASD than siblings of children without ASD [41,46-52].

Associated conditions and syndromes — A number of neurodevelopmental problems and genetic syndromes are associated with ASD [1]. Approximately 33 to 45 percent of patients with ASD have ID, as many as 50 percent have attention deficit hyperactivity disorder, and as many as 30 percent have epilepsy [23,24,53-55]. The risk of epilepsy is increased in patients with more severe ID [40].

Up to 25 percent of cases of ASD are associated with a genetic cause, many of which have well-characterized clinical features (eg, tuberous sclerosis complex [TSC], valproate embryopathy, 15q chromosome duplication) [56-61]. Associated syndromes are more common in patients with global developmental delay or ID. Any genetic syndrome that has been associated with ID can also be associated with ASD (eg, Down syndrome) [62]. Genetic diagnoses commonly associated with ASD include (table 1) [23,40,56,63,64]:

●Tuberous sclerosis complex – TSC is an inherited neurocutaneous disorder that is characterized by the development of variety of benign tumors in multiple organs. Associated clinical features include hypopigmented macules (picture 1A-B), angiofibromas (picture 2), shagreen patches (picture 3), seizures, and cognitive deficits. Approximately 40 percent of patients with TSC also have ASD; however, only 0.4 to 4 percent of patients with ASD have TSC [65-68]. Patients with comorbid TSC and ASD often have epilepsy [65,67,69,70]. (See "Tuberous sclerosis complex: Genetics, clinical features, and diagnosis".)

●Fragile X syndrome – Fragile X syndrome is an X-linked disorder that is often associated with ID. Characteristic features of the classic phenotype include a long, narrow face, prominent forehead and chin, large ears, testicular enlargement in adolescence, macrocephaly, arched palate, and hyperextensible joints. In a systematic review, 30 percent of males with fragile X syndrome had features of ASD [68]. However, fragile X syndrome is rarely found in patients with ASD [71-73]. (See "Fragile X syndrome: Clinical features and diagnosis in children and adolescents".)

●Chromosome 15q11-q13 duplication syndrome – Chromosome 15 q11-q13 duplication syndrome is characterized by hypotonia, joint laxity, global (especially motor) developmental delays, seizures, speech delay, social deficits, stereotypies, and a variable pattern of mild facial dysmorphisms [74,75]. 15q11-q13 duplication has been reported in approximately 1 to 2 percent of children with ASD, usually those with moderate to profound ID [63,76-79]. (See "Microduplication syndromes", section on '15q11-13 duplication syndrome'.)

●Angelman syndrome – Angelman syndrome is a neurodevelopmental disorder characterized by severe ID, postnatal microcephaly, and movement or balance problems. It is caused by absence of the maternally inherited copy of the UBE3A gene, which maps to chromosome 15q11-q13. In a systematic review, 34 percent of patients with Angelman syndrome had ASD [68]. (See "Microdeletion syndromes (chromosomes 12 to 22)", section on '15q11-13 maternal deletion syndrome (Angelman syndrome)'.)

●Rett syndrome – Classic Rett syndrome occurs almost exclusively in females. It is characterized by loss of speech, replacement of purposeful hand movement with stereotypic hand movement, gait abnormalities, and an abnormal respiratory pattern. In a systematic review, approximately 60 percent of females with Rett syndrome had phenomenology of ASD [68]. (See "Rett syndrome: Genetics, clinical features, and diagnosis".)

●Cohen syndrome – Clinical features of Cohen syndrome include characteristic facial features (eg, thick hair and eyebrows, wave-shaped palpebral fissures, broad nasal tip, short or smooth philtrum), microcephaly, poor weight gain in infancy, truncal obesity in adolescence, hypotonia, developmental delay, neutropenia, and joint hypermobility [80]. In a systematic review, approximately 54 percent of patients with Cohen syndrome had phenomenology of ASD [68].

●Cornelia de Lange syndrome – Cornelia de Lange syndrome is characterized by distinctive facial features (microcephaly, synophrys, highly arched eyebrows, anteverted nares), prenatal onset growth delay, hirsutism, and upper-limb reduction deficits [81]. Associated findings include hearing impairment, myopia, cardiac septal defects, gastrointestinal dysfunction, and genitourinary abnormalities. In a systematic review, approximately 43 percent of patients with Cornelia de Lange syndrome had phenomenology of ASD [68].

●Neurofibromatosis type 1 – Neurofibromatosis type 1 (NF1) is characterized by multiple café-au-lait macules (picture 4), axillary and/or inguinal freckling, Lisch nodules (iris hamartomas), and neurofibromas (picture 5). In a systematic review, approximately 18 percent of patients with NF1 had phenomenology of ASD [68]. (See "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis", section on 'Clinical manifestations'.)

●Down syndrome – Down syndrome is characterized by a variety of dysmorphic features (eg, upslanting palpebral fissures, epicanthic folds, brachycephaly), congenital malformations (eg, transverse palmar crease), ID, and other medical conditions (eg, cardiovascular disease, gastrointestinal abnormalities, endocrine disorders). In a systematic review, approximately 16 percent of patients with Down syndrome had phenomenology of ASD [68]. (See "Down syndrome: Clinical features and diagnosis".)

●Noonan syndrome – Noonan syndrome is a clinically and genetically heterogeneous condition that is associated with short stature and congenital heart disease (most often pulmonic stenosis) and delayed development. In a systematic review, approximately 15 percent of patients with Noonan syndrome had phenomenology of ASD [68]. (See "Noonan syndrome", section on 'Clinical manifestations'.)

●Williams-Beuren syndrome – Williams-Beuren syndrome is a multisystemic genetic disorder with variable phenotypic expression that is associated with "elfin" facies, systemic arterial stenosis (most often supravalvular aortic stenosis), short stature, genitourinary abnormalities, and impaired cognition and development. In a systematic review, approximately 12 percent of patients with Williams-Beuren syndrome had phenomenology of ASD [68]. (See "Williams syndrome", section on 'Clinical manifestations'.)

●DiGeorge (22q11.2 deletion) syndrome – The classic presentation of DiGeorge syndrome includes conotruncal cardiac anomalies, hypoplastic thymus, and hypocalcemia; however, the phenotype is variable (table 2). In a systematic review, approximately 11 percent of patients with 22q11.2 deletion syndrome had phenomenology of ASD [68]. (See "DiGeorge (22q11.2 deletion) syndrome: Clinical features and diagnosis".)

●PTEN (phosphatase and tensin homolog gene)-associated macrocephaly syndromes; PTEN-associated macrocephaly syndromes include:

•Macrocephaly/autism syndrome – Clinical features of macrocephaly/autism syndrome include postnatal macrocephaly, broad forehead, frontal bossing, long philtrum, depressed nasal bridge, and ID.

•Cowden/Bannayan-Riley-Ruvalcaba syndrome – Clinical features of Cowden syndrome include macrocephaly, birdlike facies, hypoplastic mandible and maxilla, cataract, microstomia, high-arched palate, pectus excavatum, genitourinary anomalies, skin tags, lipomas, and penile macules.

(See "PTEN hamartoma tumor syndromes, including Cowden syndrome", section on 'Autism spectrum disorders and macrocephaly'.)

●CHARGE syndrome – CHARGE syndrome is characterized by coloboma of the eye, heart defects, choanal atresia, growth retardation, genitourinary anomalies, and ear abnormalities. As many as 50 percent of affected patients have ASD [23,68].

●Joubert syndrome – Joubert syndrome is a heterogeneous syndrome characterized by hypoplasia of the cerebellar vermis, neurologic symptoms (eg, dysregulation of breathing pattern, developmental delay), retinal dystrophy, and renal anomalies. Approximately 40 percent of patients with Joubert syndrome also have ASD [23]. (See "Clinical manifestations, diagnosis, and treatment of nephronophthisis", section on 'Joubert syndrome'.)

●Smith-Lemli-Opitz syndrome – Smith-Lemli-Opitz syndrome is an autosomal recessive disorder of cholesterol biosynthesis [40]. Clinical features include postnatal microcephaly, soft cleft palate/bifid uvula, micrognathia, low-set posteriorly rotated ears, poor weight gain, syndactyly of the second and third toes, abnormal genitalia, ID, hypotonia, and autistic features (eg, deficits in social interaction and communication, repetitive and stereotyped behaviors) [82,83]. In one case series, 10 to 12 of 14 children with Smith-Lemli-Opitz syndrome met criteria for ASD [82].

●Timothy syndrome – Timothy syndrome is characterized by syndactyly, congenital heart disease, multiorgan dysfunction, and cognitive abnormalities. As many as 70 percent of patients with Timothy syndrome also have ASD [23].

Genetic syndromes that are not well characterized clinically may account for as many as 20 percent of cases of ASD [56]. These syndromes are characterized by incomplete penetrance and variable expressivity – which makes them difficult to identify clinically. Although there is some overlap with clinically defined syndromes, examples of such syndromes include chromosomal variations (eg, isodicentric 15q), ASD-associated copy-number variants (eg, 16p11.2 deletions or duplications), and pathogenic variants of ASD-risk genes (eg, CHD8 [chromosome helicase deoxyribonucleic acid (DNA) binding protein 8]).

PATHOGENESIS

Genetic factors — The pathogenesis of ASD is incompletely understood. The general consensus is that ASD is caused by genetic factors that alter brain development, specifically neural connectivity, thereby affecting social communication development and leading to restricted interests and repetitive behaviors [84-87]. This consensus is supported by the "epigenetic theory," in which an abnormal gene is turned "on" early in fetal development and affects the expression of other genes without changing their primary DNA sequence [88,89]. In a multinational, population-based cohort study including more than 2 million children, approximately 1 percent of whom were diagnosed with ASD by age 16 years, the estimated median heritability of ASD was 81 percent (95% CI 73-86 percent) [90]. (See "Principles of epigenetics".)

Given the complexity of ASD and the diversity of clinical manifestations, it is likely that interactions between multiple genes or gene combinations are responsible for ASD and that epigenetic factors and exposure to environmental modifiers contribute to the variable expression [91-96]. ASDs have been associated with polygenic variants, single nucleotide variants, copy number variants, rare inherited variants, tandem repeats, and noncoding variants [56,86,96-101]. (See "Genetics: Glossary of terms" and 'Associated conditions and syndromes' above.)

A strong genetic contribution to the development of ASD is supported by the unequal sex distribution, increased prevalence in siblings, high concordance in monozygotic twins, and increased risk of ASD with increased relatedness [39,51,91,92,96,102-106]. In a large population-based study, the cumulative risk of ASD by age 20 years was approximately 3 percent for cousins, 7 percent for paternal half-siblings, 9 percent for maternal half-siblings, 13 percent for full siblings and dizygotic twins, and 59 percent for monozygotic twins [39]. (See 'Male-to-female ratio' above and 'Rate in siblings' above.)

Although male predominance suggests X-linkage, male-to-male transmission in a number of families excludes X-linkage as the only mode of inheritance [91,107]. The prevalence among siblings of patients with ASD is higher than the prevalence in the general population [91,108-110] but much lower than would be expected for single-gene diseases [91]. (See 'Male-to-female ratio' above and 'Rate in siblings' above.)

The correlation between clinical phenotypes and specific genetic profiles continues to be investigated. Although linkage studies and whole exome sequencing have identified many genetic variations predisposing to ASD [44,56,111,112], no individual variation accounts for >1 percent of cases of ASD and no specific mutation is unique to ASD [40]. (See 'Associated conditions and syndromes' above.)

Neurobiologic factors — Neuroimaging, electrophysiology, and autopsy studies in patients with ASD suggest that brain abnormalities, particularly atypical neural connectivity, play an important role in the development of ASD [23,113].

Children with ASD may have accelerated head growth during infancy and increased overall brain size [114,115]. (See "Autism spectrum disorder in children and adolescents: Clinical features", section on 'Macrocephaly'.)

Compared with individuals without ASD, individuals with ASD have different total and regional gray and white matter volumes, sulcal and gyral anatomy, brain chemical concentrations, neural networks, cortical structure and organization, and brain lateralization [116-123]. Cortical changes appear to result from abnormal neuronal differentiation during prenatal development [122]. Individuals with ASD use different patterns of connectivity, cognitive strategies, and brain areas to process information during tasks requiring social attribution (eg, faces, eye gaze, speech) and social and nonsocial rewards than individuals without ASD [124-135].

Parental age — Advanced parental age (both paternal and maternal) has been associated with an increased risk of having a child with ASD [136-142]. The age comparisons vary from study to study but typically range from ≥30 to 35 years versus <30 years for mothers and ≥40 years versus <30 years for fathers. The association between advanced parental age and increased risk of having a child with ASD is perhaps related to de novo spontaneous mutations and/or alterations in genetic imprinting [143]. (See "Inheritance patterns of monogenic disorders (Mendelian and non-Mendelian)", section on 'Parent-of-origin effects (imprinting)'.)

Environmental and perinatal factors — Environmental factors include toxic exposures, teratogens, perinatal insults, and prenatal infections. They account for few cases of ASD but may constitute a "second-hit," modulating existing genetic factors predisposing to ASD [40,86,144,145]. The effects of environmental exposures appear to depend on the timing and duration of exposure, concentration of the toxin, mechanism of action, and distribution in the central nervous system.

A meta-analysis of 40 heterogeneous observational studies of perinatal and neonatal risk factors for autism found little evidence to implicate any single factor in the etiology of autism [146]. However, there was some evidence to suggest that the broad class of conditions that compromise perinatal and neonatal health (eg, abnormal presentation, low birth weight, meconium aspiration) may increase the risk. A subsequent meta-analysis of observational studies supports an increased risk of ASD in preterm infants [147]. Subsequent observational studies also suggest that maternal conditions (eg, diabetes, obesity, hypertension, preeclampsia) are associated with increased risk of ASD [148-153].

Maternal medication use during pregnancy — The potential role of maternal medication use during pregnancy in the development of ASD is discussed separately. (See "Antenatal exposure to selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs): Risk of autism in the offspring" and "Risks associated with epilepsy during pregnancy and the postpartum period", section on 'Risks with specific ASMs'.)

Lack of association with immunizations — Epidemiologic evidence does not support an association between immunizations and ASD. (See "Autism spectrum disorder and chronic disease: No evidence for vaccines or thimerosal as a contributing factor".)

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SUMMARY

●Terminology – Autism spectrum disorder (ASD) is a biologically based neurodevelopmental disorder characterized by persistent deficits in social communication and interaction and restricted, repetitive patterns of behavior, interests, or activities. Symptoms become apparent when social demands exceed limited capacities. Severity is determined by functional impairment and can be critical in the ability to access services. (See 'Terminology' above.)

●Prevalence – Estimates of prevalence vary with study methodology and the population that is evaluated and range from 1 in 40 to 1 in 500. The prevalence of ASD has increased over time, particularly since the late 1990s, primarily as a result of changes in case definition and increased awareness. In the United States, national surveillance suggests a prevalence of approximately 1 in 40 to 1 in 60. (See 'Prevalence' above.)

●Associated conditions and syndromes – Intellectual disability, attention deficit hyperactivity disorder, and epilepsy are common in children with ASD. ASD is more common among children with certain genetic conditions than in the general population (table 1). These conditions include tuberous sclerosis complex, fragile X syndrome, chromosome 15q11-13 duplication syndrome, Angelman syndrome, Rett syndrome, Down syndrome, Cohen syndrome, Cornelia de Lange syndrome, Neurofibromatosis type 1, Noonan syndrome, Williams-Beuren syndrome, DiGeorge (22q11.2 deletion) syndrome, PTEN-associated macrocephaly syndrome, CHARGE syndrome, Joubert syndrome, Smith-Lemli-Opitz syndrome, and Timothy syndrome. (See 'Associated conditions and syndromes' above.)

●Pathogenesis – The pathogenesis of ASD is incompletely understood. The general consensus is that ASD is caused by genetic factors that alter brain development resulting in the neurobehavioral phenotype. Environmental and perinatal factors account for few cases of ASD but may modulate underlying genetic factors. (See 'Pathogenesis' above.)

The overwhelming majority of epidemiologic evidence does not support an association between immunizations and ASD. (See "Autism spectrum disorder and chronic disease: No evidence for vaccines or thimerosal as a contributing factor".)