Description

General principles. Fundamental to understanding the science of child development is the notion that it is a dynamic, fluid process resulting from a predictable and orderly nervous system evolution beginning in the fetal period and proceeding through the lifespan. Normal development is the result of both the orderly development of neuroanatomy, which is dependent on the appropriate organization and signaling at the right time with an absence of disruption or dysfunction, as well as an appropriate environment that provides sufficient input (including nutrition, learning opportunities, and social-emotional connections) for ongoing growth.

Development is subdivided into several streams centered on functional skills that can be measured and compared over time (gross and fine motor, speech and language, and social and personal skills, as well as activities of daily living) (73). Developmental delay can affect any of these streams. At older ages (generally starting at school age), when testing is more reliable and predictive, cognition can be further subdivided into areas of intellectual functioning, such as memory, verbal comprehension, visuospatial reasoning, expressive language, fluid reasoning, executive functioning, and adaptive functioning. Elucidating the pattern of deficits is important for diagnosis, guiding investigations, and remediation through intervention and accommodations.

Motor development. Gross motor development involves full-body movements of the trunk and legs, culminating in independent walking, running, and climbing. Fine motor skills primarily involve the shoulder, arms, and hands, allowing refined skills such as grasping, writing, and throwing. These skills increasingly merge with visual skills into drawing and construction, allowing the testing of visual-motor-based problem solving, a core function of intellectual development. Normal motor development progresses from cephalad to caudad, with refinement of upper body movements progressing before those of the lower body. Delays in motor development range from high prevalence minor neuromotor abnormalities and coordination disorders to more severe and lower prevalence disorders such as cerebral palsy, spinal cord abnormalities, muscular dystrophies, and myopathies. Motor delays may also be a marker for other neurodevelopmental disabilities, chronic illnesses, or visual impairment. Infant hypotonia and delays in reaching motor milestones are common and can be the first sign in children with genetic disorders and associated intellectual disabilities, but they can also be seen in children with otherwise normal cognitive development (51).

Speech and language development. Language refers to a system of learned abstract symbols and rule-governed structures used to send and receive messages. Language is typically subdivided into receptive, expressive, and pragmatic language. Receptive language is the efficient understanding of these symbols and rules. Language delay is often the most recognizable reflection of intelligence in development for parents and professionals in young children. Expressive language involves the expression of symbols and rules. Pragmatic language refers to the ability to use language appropriately within a social, situational, and communicative context. In the development of pragmatics, a child acquires the ability to use language in a social context. Importantly, language development begins even before children use their first word. Protophones are vocalizations, not including cries and laughs, that start on the first day of life and continue through the first year of life. Precanonical protophones include vowel-like sounds (vocants), growls, and squeals during the first half-year of life. Canonical syllables occur in the second half of the first year and are composed of consonant-vowel combinations, such as “na” and “da” (52).

Social and personal skills. Social development requires language and problem-solving skills but is more heavily dependent on appropriate verbal and nonverbal communication and is often associated with pragmatic communication deficits. Other areas of social skills include the ability to understand, build, and maintain appropriate interpersonal relationships. In children, this includes appropriate play skills and the ability to modulate behavior appropriately for the social context. As they progress in personal emotional recognition, regulation and modulation of emotions become more important. Delays in social skills are seen in children with intellectual disorders, communication disorders, and autism spectrum disorders.

Activities of daily living. Activities of daily living, including personal hygiene, cooking, cleaning, and handling money, are a subset of adaptive functioning that also includes communication, social, and relationship skills. The development of adaptive skills occurs in parallel to the other development streams. They depend on motor, language, and intellectual skill development and are subject to environmental and cultural influences. Delays in achieving milestones in activities of daily living such as feeding, toileting, and dressing do not directly infer diagnoses but provide further evidence for suspected diagnoses. A delay in adaptive functioning is necessary to diagnose intellectual disability in DSM-5.

Definitions. In developmental disorders, the timing, order, or sequence of acquiring specific readily recognizable skills, commonly referred to as milestones, is disturbed. The assessment of abnormal development employs the principles of delay, deviance, dissociation, and regression (01). Abnormal development can be seen in the pattern of slowed development, where progress continues with steady progress that is behind what is expected for age. Milestones or proficiency of skills are reached at a significantly later age than average (usually defined as two or more standard deviations behind population norms). This pattern is generally implied when development is referred to as “delayed.”

Other abnormal development patterns include plateau, where skills no longer progress, or regression, where previously acquired skills are lost. It can be difficult to distinguish between delay and plateau or regression when observed at a single time point. However, it is important to identify developmental plateaus or regression, even when they may coexist with a preexisting delay because these patterns suggest different etiologies (for example, neurodegenerative, neoplastic, metabolic, or autoimmune) that require specific investigations and interventions. Dissociation describes differing rates of development across the five streams of function. For example, a child with intellectual disability may have a delay in speaking skills but walk independently at a typical age. Deviance occurs when a child acquires milestones out of the usual sequence within a single stream of development. For example, a child who crawls before sitting unsupported demonstrates deviant gross motor skills; in language development, deviance is demonstrated in the use of idiosyncratic language in autism spectrum disorders.

The DSM-5 divides intellectual disorders into intellectual disability, global developmental delay, and unspecified intellectual disability. Global developmental delay is reserved for children younger than 5 years of age who show significant delays (scores two or more standard deviations below the mean) in two or more of the following developmental domains: fine/gross motor skills, speech/language, social or personal skills, and activities of daily living. Typically, children with global developmental delay show delays across most or all domains of functioning. Intellectual disability is defined as deficits in intellectual functions (reasoning, problem-solving, planning, abstract thinking, judgment, academic learning) on both clinical assessment and standardized testing and deficits in adaptive functioning that result in failure to meet developmental and sociocultural standards for independence and social responsibility. These deficits must have onset in the developmental period. Intellectual disability is classified as mild, moderate, severe, or profound based on the severity of deficits in adaptive functioning and can be further described based on associated medical conditions, genetic conditions, or environmental factors. Unspecified intellectual disability refers to individuals over the age of 5 years who have a history and clinical presentation consistent with cognitive impairment but are not suitable for standardized intellectual testing and, therefore, cannot meet the criteria for intellectual disability (63).

A specific learning disorder refers to difficulties in learning in a specific area, where academic skills are behind (2 or more grades) what is expected for age in the context of otherwise normal intellect, ie, achievements in a particular skill (eg, reading) are deficient and out of keeping with IQ (would be diagnostic of a specific learning disorder in reading).

Epidemiology. In 2016, 52.9 million children (or 8.4%) younger than 5 years of age had developmental disabilities worldwide, with approximately 95% living in low- and middle-income countries. Sensory deficits (hearing and vision loss) accounted for 40.7 million children with disabilities, followed by intellectual disability and autism spectrum disorder, accounting for 12.5 and 4.6 million, respectively; however, intellectual disability accounted for the most years lived with disability (28).

The differential diagnosis for developmental delay includes:

	• Isolated developmental delay
	• Neurologic disease or injury
	• Inborn errors of metabolism and other progressive medical concerns
	• Teratogenic or toxic exposure
	• Chromosomal disorders
	• Genetic syndromes
	• Other neurodevelopmental disorders (eg, autism spectrum disorder, attention deficit hyperactivity disorder)
	• Specific learning disabilities
	• Other mental health disorders
	• Medical diagnoses
	• Sensory impairment
	• Socioeconomic deprivation

Clinical applications

Identification: developmental surveillance and screening. Identifying and evaluating a child with a suspected developmental disorder typically begins with concern regarding a delay in the child’s acquisition of developmental skills. Such concern may arise directly from the parent. In fact, parental concern has been demonstrated to predict lower standard scores and to accurately identify major delays (17; 38; 15). Another source is through surveillance and screening by the primary care health provider during ongoing well-child care. Current recommendations for the early identification of developmental disorders by the American Academy of Pediatrics include:

	(1) Performance of developmental surveillance at every preventive visit
	(2) Administration of a standardized developmental screening test to all children at the 9-, 18-, and 24- or 30-month preventive care visits
	(3) Administration of a standardized developmental screening test when concerns arise through surveillance (04).

When developmental surveillance and screening suggest the possibility of a developmental disorder, further medical and developmental evaluation should be performed to establish the extent of concern and to initiate evaluation for an underlying etiology.

Developmental surveillance. Developmental surveillance is a flexible, longitudinal, continuous, and cumulative process performed over time (04). The clinician inquires about developmental concerns, identifies key historical risk factors, and obtains a developmental history of milestone achievement from the parent. Informal observations of a child’s development are made during the physical examination. As much as the clinical environment allows, developmental surveillance should include direct observation of developmental skills attainment over time. The child health care provider should suspect a developmental problem when a child shows consistent delay in one or more development streams or when deviancy or regression are observed. When such concerns arise, the child should be referred for formal developmental evaluation.

Developmental screening. Developmental screening is a more formal procedure performed on all children discretely during preventive health care. It employs standardized screening tests to identify children needing further evaluation for a developmental disorder and can be for generalized development or specific disorders. Screening does not result in a diagnosis but can alert medical professionals to the need for further evaluation. A child may be assigned a risk category rather than continuous standard scores. Those in the suspect category typically require more frequent surveillance or screening, whereas those at highest risk require more detailed developmental and medical testing. No specific screening tool is recommended. The appropriate tools should be chosen for reliability and sensitivity in the population being considered and for feasibility and sustainability in the clinical context (04).

Developmental evaluation. Developmental assessment is a more complex process aimed at identifying specific developmental disorders. It consists of developmental testing in each development stream, with interpretation of any abnormal patterns (eg, delay, deviancy, dissociation, and regression). This may require involvement of multidisciplinary expertise for appropriate testing in each of the developmental streams. Delays in language and nonverbal abilities on both history and evaluation, accompanied by a history of delays in adaptive skills, suggest a diagnosis of intellectual disability. Delays in language development with normal nonverbal skills (dissociation) imply a communication disorder diagnosis.

Developmental disorders present to professionals at varying points in time, depending on the affected stream of development and the severity of the delay. Children with severe motor disabilities typically present with an absence of rolling or sitting in infancy. When mild, the toddler may have a delay in onset of independent walking or deviant toe-walking. The child with a communication disorder, including autism, or an intellectual disorder may present to the physician as early as 18 months with absence of early vocabulary development, interest in others, use or response to name or pointing, imitation, or following of simple verbal requests. Others with communication or intellectual disabilities may present between ages 2 to 3 years when vocabulary fails to grow, short sentences are not formed, or verbal requests cannot be followed. Isolated learning disorders are not apparent until children fail to acquire academic achievement at school age.

Evaluation of the child with developmental delay. The medical consultative evaluation is typically performed by child neurologists who are also neurodevelopmental disabilities specialists, developmental and behavioral pediatricians, child neurologists, pediatricians with experience in neurodevelopmental disabilities, or others with expertise in medical genetics or physical medicine and rehabilitation. The aims are identifying developmental diagnoses, recognizing an underlying etiology, offering prognostic information, and initiating appropriate therapy and ongoing medical treatment of related problems. With improved identification of monogenic intellectual disabilities and understanding of the cellular pathways involved (eg, everolimus for tuberous sclerosis), there are several emerging treatments that may hold promise for targeting the underlying disorders, increasing resolve to find etiologies for developmental disorders (73).

Patient history. The consultative medical evaluation of the child with delayed development begins with a comprehensive review of the developmental history. Using the core principles of delay, dissociation, deviance, and regression through identification of the ages of milestone acquisition, coupled with measurement of developmental quotient, the developmental history provides clues to the developmental diagnosis. Additional behavioral history can reveal abnormal patterns of social or play behaviors, with reports of hyperactivity, impulsivity, noncompliance, aggression, destruction, stereotypy, solitary play, or self-injury.

A comprehensive medical history provides valuable information on etiology and management guidance. The cause of cognitive or developmental delay can be identified in approximately one third of children based on history and physical exam alone (72). History should include prenatal history for exposure to teratogens, intrauterine infections, or other risks (eg, gestational diabetes or pregnancy-related hypertension). History of documentation of complications during labor or delivery should be sought as well as neonatal complications such as prematurity, intraventricular hemorrhage, periventricular leukomalacia, seizures, retinopathy, or hypoxic-ischemic encephalopathy (49). Information on medical illnesses or surgical procedures can identify developmental risk factors such as serious infections, head trauma, seizure disorders, congenital anomalies, and chronic medical, metabolic, or endocrine disorders. A full review of systems could provide information relevant to etiology and co-occurring conditions that need to be addressed. This includes descriptions of diet, sleep, mental health concerns, and recurrent or chronic pain. A child’s family history can reveal relatives with related genetic, developmental, learning, or intellectual disorders. Social history is useful for understanding related family risk and protective factors and offers insight into the current level of support. Various patterns of developmental abnormalities can be observed in cases of neglect, abuse, or deprivation (09). Identifying current family stressors, such as problems in health, employment, marriage, physical abuse, or substance abuse, is important to assist the family in receipt of community services and support and, therefore, to minimize such problems and their effect on the child and family.

Physical examination. Performance of a comprehensive physical examination can further assist in identifying related medical conditions. The examination should include growth measurement and general physical and neurologic examinations. Comparison of weight, height, and head circumference to age norms can assist in identifying conditions and syndromes associated with failure to thrive, short stature, overgrowth, obesity, microcephaly, and macrocephaly. The general physical exam can identify congenital anomalies or markers of an underlying genetic disorder, such as neurocutaneous lesions, midline defects, cardiac anomalies, or genitourinary findings. Dysmorphic features of the head, face, ears, or hairline suggesting genetic disorders may be seen. In infants and young children, the neurologic examination should include classic elements evaluating cranial nerve function, tone, strength, and reflexes but should also assess reactivity and level of consciousness, motor function as well as the pathological, primitive, and postural reflexes that emerge or diminish through the course of normal development (13; 30). In the older ambulatory child, evaluation of gait quality, functional movement, and fine motor movement provides additional information. In the school-age child, soft or subtle signs, such as mild axial hypotonia, synkinesia, or dyskinesia, as observed while doing repetitive hand movements or walking with a stressed gait, may accompany disorders of communication, learning, and ADHD (70; 16; 45; 53).

Developmental evaluation. Developmental evaluation is a critical part of the comprehensive evaluation and must be tailored to the age and presentation of the child, as well as the current treatment, education, or social needs. Evaluations by related professionals in the fields of psychology, early childhood education, speech-language pathology, audiology, physical therapy, occupational therapy, and social work may offer information useful to making a diagnosis as well as provide information regarding a child’s therapeutic and educational needs and related child and family support. Various instruments are commercially available, ranging from comprehensive measures of several domains to measures of specific domains, such as articulation. The clinician must choose tests based on the child’s age, the area of development, the psychometric properties of the test, and the time required for administration. The Capute Scales (02), the Battelle Developmental Inventory (50), and the Mullen Scales of Early Learning (46) are valid multi-domain evaluations in the infant, toddler, and preschooler. In school-aged children with academic concerns, achievement tests, such as the Wide-Range Achievement Test (74), can clarify reading, arithmetic, and spelling abilities. Formal psychological measures of intelligence should be performed by psychologists when a child is suspected of having an intellectual or learning disability. Behavior typically is assessed through parent or teacher questionnaire completion and can be broad-based, looking at a wide range of behaviors, or diagnosis-targeted such as autism- or ADHD-specific questionnaires. Behavior observation in different contexts may also be undertaken, particularly if there are differing reports across environments.

Investigations. Formal assessment for sensory impairments should be performed to exclude sensory impairments as a cause for developmental abnormalities and look for markers of associated conditions in possible syndromic conditions that include developmental delays. Sensory impairments are typically identifiable during the first year of life. The vision-impaired child will fail to fix and follow objects by 3 months of age. The hearing-impaired child who is not identified during newborn hearing screening can be recognized with a lack of response to sound or turning to voice during the first 6 months or through the absence of saying “mama” or “dada” but can be missed when hearing impairment is not complete or is progressive.

Laboratory investigation. Metabolic disorders should also be investigated if there is a history of periodic change, loss of skills, or precipitation of symptoms by illness. Newborn screening detects many inborn errors of metabolism, but because these conditions are potentially treatable, and we do not know the false-negative rate of newborn screening in many cases, it is also important to consider them during evaluation (71; 43). If children have been born in jurisdictions where newborn screening is not routine, comprehensive laboratory tests for inborn errors of metabolism should be considered early in evaluation. Serum lead and thyroid function tests should be considered in the appropriate context (44) and ferritin is commonly recommended in cases of dietary restriction in association with developmental delays (43).

Genetic investigations. Identifying a specific diagnosis may inform treatment decisions, allow for specific anticipatory guidance, and provide recurrence-risk information for family planning. For this reason, evaluation for developmental delay and autism spectrum disorders includes genetic work-up. If a specific genetic syndrome is suspected based on the rest of the examination, the appropriate test should be sent. However, in cases where the clinical history, family history, physical exam, and developmental exam do not suggest a specific disorder, chromosomal microarray is considered first-line evaluation (42; 20; 62; 44). In a query of the International Standards for Cytogenomic Arrays Consortium database, at least 7% of the cases had a diagnosis leading to specific clinical management implications (60), but some reports indicated a diagnostic yield up to 20% (39). Analysis of FMR1 for fragile X is currently recommended in guidelines for all boys and girls in whom the cause of their developmental delay is unknown as first-line testing with microarray. However, the prevalence of all other X-linked disorders exceeds fragile X (44), and some guidelines recommend testing only in select cases (29). MECP2 for Rett syndrome should be considered in girls in the right clinical setting. Second-tier genetic testing for single gene disorders or gene panels can be added based on the clinical picture, such as X-linked intellectual disability panels in boys. Whole exome or whole genome sequencing are emerging technologies that are becoming much more widely available. Some tertiary centers have reported diagnostic hit rates of 40% to 68% for children with developmental disabilities and other features suggestive of a genetic cause, dysmorphisms, other organ system abnormalities, abnormal neuroimaging, etc. (62; 66; 68). Whole exome or whole genome sequencing holds promise for the evaluation of developmental disabilities, but because of the complexity of interpreting and reporting these tests, it should only be done by experienced clinicians after extensive genetic counseling with the families. Recently, whole exome sequencing has been recommended as a first-tier clinical test (67).

Neuroimaging. MRI of the brain as a tool to investigate global developmental delay is controversial. MRI remains a resource-intensive investigation, and although there is little risk involved in MRI, there is a small risk associated with general anesthetic required in young children. There is a wide range of reported rates of abnormalities (0% to 98%), but it is often recommended to investigate for underlying etiology if developmental delay is severe, affecting multiple domains, or if there are any other neurologic signs or symptoms (eg, epilepsy) (29; 47). Neuroimaging should be considered when examination reveals significant motor findings or focal neurologic abnormalities or when microcephaly, macrocephaly, or changing head circumference growth velocity is seen. In children with idiopathic cerebral palsy, the American Academy of Neurology and Child Neurology Society recommend neuroimaging, preferably with MRI (06). CT is not recommended for the evaluation of developmental delay.

Other. Further investigations should be tailored to specific indications that may arise during a comprehensive medical history and physical exam. An EEG is recommended only if there is suspicion of seizure or patterns suggestive of specific epilepsy syndromes (64).

Treatments and interventions.

Management of the child with developmental delay. After completing a comprehensive medical and developmental evaluation of the child with developmental problems, establishing developmental diagnoses, and identifying associated medical conditions, the physician can initiate a plan for active treatment and comprehensive management. Beginning with early identification of these problems, an affected child can receive educational and intervention services aimed at improving the child’s development through local early intervention and special education programs. These should not be delayed by ongoing investigations into the possible etiology of the delay if that is required. Internationally, the rights of children with disabilities are recognized in Article 23 of the United Nations Convention on the Rights of the Child, which was ratified by 198 countries (every member state of the United Nations except the United States) and entered into force in September 1990 (14). It asserts that children with disabilities should “enjoy a full and decent life” and receive “education, training, health care services, rehabilitation services, preparation for employment and recreation opportunities.” The rights of children with disabilities to life, education, and community participation were further emphasized in the 2008 United Nations Convention on the Rights of Persons with Disabilities. Within the United States, access to early education and intervention services aimed at improving the child’s development through local intervention and special education programs was established through federal law under the Individuals with Disabilities Education Act (32).

Beginning as early as birth and continuing through age 3 years, any child with a known disability, significant delay, or condition with a high risk for disability (eg, Down syndrome) is entitled to early intervention services that provide developmental therapies intended to improve performance in one of the developmental spheres. These can include traditional therapies, such as physical therapy, occupation therapy, and speech-language therapy, as well as broader services, such as special instruction, counseling, and family training. Many programs provide parent training or home-based therapy to allow for generalization of skills learned (12; 61). For children 3 years and older and continuing into the school-age years, children with disabilities should have access to individualized, free, and appropriate education along with related therapy services (05; 37).

Specific medical treatments targeted towards a child’s related medical conditions are also important. Children with cerebral palsy should be considered for medical treatment of tone abnormalities with oral agents, intramuscular botulinum toxin, or intrathecal baclofen in addition to receiving physical therapy (48; 11; 08; 65). Children with early-onset epilepsy associated with tuberous sclerosis complex may have better developmental outcomes with early intervention using medications that target the disease neurobiology (27; 34). Careful screening for other co-occurring and potentially interfering conditions, particularly those that could interfere with optimal development, should be undertaken continuously. For example, dental issues are common in children with disabilities, can result in pain and interfere with behavior and sleep, and may require specialized care (35). Up to 80% of children with neurodevelopmental disabilities are reported to have sleep disorders (03; 10).

Children with communication or intellectual disabilities who demonstrate comorbid behavior disorders may benefit from psychopharmacologic treatments, such as stimulants for ADHD (69). A meta-analysis of the treatment of children with ADHD indicated high-quality evidence that psychostimulants (formulations of methylphenidate or amphetamine) have a moderate-to-large effect on oppositional behavior, cognitive problems, and aggression symptoms. Other ADHD medications (alpha-2 agonists or atomoxetine) have a small to moderate effect on these symptoms (56). Risperidone and aripiprazole have evidence in treating aggression in children with autism spectrum disorder (59; 22) but require regular clinical and laboratory monitoring to ensure safety (55). Based on a systematic review, there is moderate-quality evidence that risperidone has a moderate-to-large effect on conduct problems and aggression in youth with below-average IQ, with and without ADHD, and high-quality evidence that risperidone has a moderate effect on disruptive and aggressive behavior in youth with average IQ and oppositional defiant disorder or conduct disorder, with and without ADHD (57).

Finally, children with a developmental disability should have a medical home as a child with special health care needs (41; 05; 31). This allows the primary care provider a chronic condition management program to monitor regular health for chronological age and to provide anticipatory guidance for developmental age. In cases where complex care management is required, some centers have implemented specific care coordination services that can assist with planning of multiple services and supports, which have been shown to improve care access, needs met, and family empowerment (40). Specialized, condition-related office visits, written care plans, explicit co-management with medical specialists, appropriate patient education, and an effective monitoring and tracking system should be implemented. Ongoing surveillance for other behavioral, mental health, and developmental concerns should also be undertaken on an ongoing basis. It has been shown that individuals with developmental concerns have a high incidence of these co-occurring mental health conditions and that they can go unrecognized due to diagnostic overshadowing (58).

Psychosocial education and support should incorporate the caregivers and families of children with developmental disorders. Both the primary care physician and the specialist can refer the family to community-based support services, such as respite care, parent-to-parent programs, and advocacy organizations. Parent organizations and condition-specific organizations can provide further family support, assistance, and information, including information on specific community services (26). Some children will qualify for additional benefits, and physicians or multidisciplinary support (such as social workers) in the child’s medical home should be informed about these additional services and their qualifications. As children become young adults and transition to adult services, there can be an increased burden on families and caregivers of people with intellectual disabilities. Transition resources should be employed where available to ensure ongoing support of individuals’ needs (18).